Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same

ABSTRACT

An object of the present invention is to provide crystal of a cyclic phosphonic acid sodium salt (2ccPA) with high purity and excellent storage stability and a method for producing the crystal. The present invention provides a crystal of a cyclic phosphonic acid sodium salt (2ccPA) represented by formula (1):

TECHNICAL FIELD

The present invention relates to a crystal of a cyclic phosphonic acidsodium salt and a method for producing the crystal.

BACKGROUND ART

The cyclic phosphonic acid sodium salt (a sodium salt of 9-octadecenoicacid (9Z)-(2-hydroxy-2-oxo-2λ⁵-1,2-oxaphosphoran-4-yl)methyl ester)represented by the following formula (1) is a compound, typicallyreferred to as 2ccPA.

2ccPA is known to have a potent analgesic action (Patent Literature 1)and is also expected to serve as an anti-cancer agent because of itsinfiltration-inhibitory activity on cancer cells (Patent Literature 2),an osteoarthritis therapeutic agent because of its acceleratedproduction of hyaluronic acid (Patent Literature 3), or other agents.

2ccPA has traditionally been produced by the production method shown inthe following reaction scheme-1 (Patent Literature 2 and 4 andNon-patent Literature 1 and 2).

Specifically, iodine compound (5a), which is obtained by the productionmethod disclosed in Non-patent Literature 2, is first reacted withtrimethyl phosphite to prepare dimethyl phosphonate (6a). Subsequently,p-toluenesulfonic acid (p-TsOH) is allowed to act on compound (6a) toobtain compound (8a). After oleic acid is introduced to compound (8a) toprepare compound (9a), demethylation is performed, and further a sodiumsalt is formed, thereby producing 2ccPA.

However, because of the absence of optimization of the reactionconditions for each step and the need for purification by silica gelcolumn chromatography in each step, the total yield of 2ccPA in thisproduction method, obtained by performing the 5 steps described above,is as low as 18.7%, when calculated from the yields disclosed in theliterature. This indicates that the method is not suitable for synthesison a large scale. In addition, the use of bromotrimethylsilane (TMSBr)in the demethylation step generates hydrogen bromide as a by-product,which makes the reaction system strongly acidic, making the productprone to decomposition. In actuality, the yield in the demethylationstep is as low as 38%.

In the final step, compound (10a) is formed into a sodium salt using asodium hydroxide aqueous solution to induce 2ccPA. However, becausefreeze-drying is performed without purification, strongly basic sodiumhydroxide may come to be mixed with the solid of 2ccPA. Thus,decomposition of 2ccPA by sodium hydroxide is unavoidable, causing astorage stability problem.

Therefore, there has been a demand for the development of a method forproducing a crystal of 2ccPA that is convenient, and that produces ahigh-purity crystal exhibiting excellent storage stability at a highyield, as compared with the traditional known method.

CITATION LIST Patent Literature

-   Patent Literature 1: U.S. Pat. No. 5,077,893-   Patent Literature 2: JP2004-10582-   Patent Literature 3: WO2013/069404-   Patent Literature 4: WO03/104246

Non-Patent Literature

-   Non-patent Literature 1: Biochimica et Biophysica Acta, 2007, 1771,    pp. 103-112-   Non-patent Literature 2: Tetrahedron, 1991, Vol. 47, No. 6, pp.    1001-1012

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a crystal of 2ccPA withhigh purity and excellent storage stability.

Another object of the invention is to provide a method for producing thecrystal of 2ccPA that is convenient and that produces the crystal at ahigh yield.

Solution to Problem

The present inventors conducted extensive research to achieve theobjects, and produced at a high yield a cyclic phosphonic acid ester,which is a precursor of 2ccPA, performing only one-time purification bysilica gel column chromatography, and successfully induced 2ccPA fromthe cyclic phosphonic acid ester without using a strong acid or strongbase.

In addition, the inventors found that the thus-produced crystal of 2ccPAis excellent in storage stability and can achieve the objects. Thepresent invention was completed on the basis of these findings.

Specifically, the present invention provides the following crystal of2ccPA and the method for producing the crystal.

Item 1. A crystal of a cyclic phosphonic acid sodium salt (2ccPA)represented by formula (1):

Item 2. The crystal according to Item 1, having an X-ray powderdiffraction spectrum comprising a characteristic peak expressed indegrees 2θ at 15° to 17°.Item 3. The crystal according to Item 1 or 2, having an X-ray powderdiffraction spectrum comprising a characteristic peak expressed indegrees 2θ at 9° to 10°.Item 4. The crystal according to any one of Items 1 to 3, having anX-ray powder diffraction spectrum comprising characteristic peaksexpressed in degrees 2θ at 3° to 5°.Item 5. The crystal according to Item 4, having an X-ray powderdiffraction spectrum comprising characteristic peaks expressed indegrees 2θ at 4.7° to 5.0°.Item 6. The crystal according to Item 4, having an X-ray powderdiffraction spectrum comprising a characteristic peak expressed indegrees 2θ at 4.4° to 4.6°.Item 7. The crystal according to Item 4, having an X-ray powderdiffraction spectrum comprising a characteristic peak expressed indegrees 2θ at 4.1° to 4.30.Item 8. The crystal according to Item 4, having an X-ray powderdiffraction spectrum comprising a characteristic peak expressed indegrees 2θ at 3.7° to 3.9°.Item 9. The crystal according to any one of Items 1 to 8, having amelting point of 187 to 190° C.Item 10. A method for producing the crystal according to any one ofItems 1 to 9, the method comprising

step (H) of reacting a cyclic phosphonic acid ester represented byformula (9):

wherein R¹ represents alkyl, arylalkyl, or aryl with a sodium halide inan organic solvent to obtain 2ccPA, and

step (I) of concentrating a solution containing the 2ccPA obtained instep (H) under reduced pressure, or cooling the solution containing the2ccPA obtained in step (H) to precipitate the crystal.

Item 11. The method for producing the crystal according to Item 10, themethod further comprising

step (J) of dissolving the crystal obtained in step (I) in water and/oran organic solvent to obtain a solution, and

step (K) of adding a poor solvent to the solution obtained in step (J)to perform recrystallization.

Item 12.

A crystal of a cyclic phosphonic acid sodium salt (2ccPA) obtained bythe method according to Item 10 or 11.

Item 13. A method for producing a crystal of a cyclic phosphonic acidsodium salt (2ccPA) represented by formula (1):

the method comprising

step (H) of reacting a cyclic phosphonic acid ester represented byformula (9):

wherein R¹ represents alkyl, arylalkyl, or aryl with a sodium halide inan organic solvent.Item 14. A method for producing a cyclic phosphonic acid esterrepresented by formula (9):

wherein R¹ represents alkyl, arylalkyl, or aryl, the method comprising

step (G) of reacting a compound represented by formula (8):

wherein R¹ is as defined above with an oleic acid compound.Item 15. A method for producing a compound represented by formula (8):

wherein R¹ represents alkyl, arylalkyl, or aryl, the method comprising

step (F) of allowing a base to act on a compound represented by formula(7):

wherein two R¹ groups are the same or different and represent alkyl,arylalkyl, or aryl.Item 16. A method for producing a compound represented by formula (7):

wherein two R¹ groups are the same or different and represent alkyl,arylalkyl, or aryl, the method comprising

step (E) of allowing an acid to act on a compound represented by formula(6):

wherein R¹ is as defined above; and two R² groups are the same ordifferent and represent alkyl, cycloalkyl, or aryl.Item 17. A method for producing a compound represented by formula (6):

wherein two R¹ groups are the same or different and represent alkyl,arylalkyl, or aryl; and two R groups are the same or different andrepresent alkyl, cycloalkyl, or aryl, the method comprising

step (D) of reacting a compound represented by formula (5):

wherein R^(z) is as defined above; and X represents a halogen atom witha phosphorous acid diester.Item 18. A method for producing a halogen compound represented byformula (5):

wherein two R² groups are the same or different and represent alkyl,cycloalkyl, or aryl; and X represents a halogen atom, the methodcomprising

step (C) of reacting a compound represented by formula (4):

wherein R² is as defined above; and R³ represents substituted orunsubstituted alkyl or substituted or unsubstituted aryl

with an alkali metal halide and/or an alkaline-earth metal halide in thepresence of a base.

Item 19. A method for producing a compound represented by formula (4):

wherein two R² groups are the same or different and represent alkyl,cycloalkyl, or aryl; and R³ represents substituted or unsubstitutedalkyl or substituted or unsubstituted aryl, the method comprising

step (B) of reacting a compound represented by formula (3):

wherein R² is as defined above with a sulfonyl halide compound.Item 20. A method for producing a compound represented by formula (5):

wherein two R² groups are the same or different and represent alkyl,cycloalkyl, or aryl; and X represents a halogen atom, the methodcomprising

step (B′) of reacting a compound represented by formula (3):

wherein R² is as defined above with a halogenating agent.Item 21. The method for producing the crystal according to Item 10 or13, the method further comprising the step of any one of Items 14 to 20.

Advantageous Effects of Invention

The crystal of 2ccPA according to the present invention is excellent instorage stability, and does not significantly decompose when stored fora long period of time.

Following the production method of the present invention, a high-puritycrystal of 2ccPA can be produced at a high yield in a simple manner.

Specifically, the production method of the present invention includes anovel production method, and, in particular, the present invention canproduce a cyclic phosphonic acid ester, which is a precursor of 2ccPA,without performing isolation and purification in each step(Telescoping).

The production method of the present invention also reduces the risk ofdecreases in purity without using a strong acid or strong base, andproduces a crystal of 2ccPA excellent in stability from the cyclicphosphonic acid ester in a simple manner.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 1.

FIG. 2 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 2.

FIG. 3 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 3.

FIG. 4 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 4.

FIG. 5 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 5.

FIG. 6 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 6.

FIG. 7 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 7.

FIG. 8 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 8.

FIG. 9 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 9.

FIG. 10 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 10.

FIG. 11 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 11.

FIG. 12 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 12.

FIG. 13 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 13.

FIG. 14 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 14.

FIG. 15 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 15.

FIG. 16 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 16.

FIG. 17 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 17.

FIG. 18 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 18.

FIG. 19 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 19.

FIG. 20 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 20.

FIG. 21 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 21.

FIG. 22 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 22.

FIG. 23 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 23.

FIG. 24 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 24.

FIG. 25 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 25.

FIG. 26 illustrates an X-ray powder diffraction spectrum of the crystalof 2ccPA obtained in Example 26.

FIG. 27 is a graph illustrating the results of a stability test.

DESCRIPTION OF EMBODIMENTS

The following describes in detail a novel crystal of 2ccPA and a methodfor producing the crystal according to the present invention.

In this specification, the term “comprise” includes the concept of“comprise,” “consist essentially of,” and “consist of.”

1. Crystal of Cyclic Phosphonic Acid Sodium Salt (2ccPA)

The crystal of 2ccPA of the present invention is a crystal of a cyclicphosphonic acid sodium salt (a sodium salt of 9-octadecenoic acid(9Z)-(2-hydroxy-2-oxo-2λ⁵-1,2-oxaphosphoran-4-yl)methyl ester; IUPACname:4-[(Z)-octadec-9-enoyloxymethyl]-2-oxo-1,2-λ⁵-oxaphosphorane-2-olatesodium salt).

The crystal of 2ccPA exhibits a characteristic peaks in the followinglattice spacing (d) in an X-ray powder diffraction spectrum obtainedwith monochromated copper radiation (λ=1.54059 Å), as measured with, forexample, a RINT-2000 Ultima IV (produced by Rigaku Corporation, tradename).

The crystal of 2ccPA has a crystal X-ray powder diffraction spectrumcomprising a characteristic peak(s) expressed in degrees 2θ at about 15°to 17° (hereinafter, “peak A”), a characteristic peak expressed indegrees 2θ at about 9° to 10° (hereinafter “peak B”), or at least onecharacteristic peak expressed in degrees 2θ at about 3° to 5°(hereinafter “peaks C to F”).

The peaks C to F further comprise the following peaks C, D, E and/or F:

characteristic peaks at about 4.7° to 5.0° (hereinafter, “peak C”)

a characteristic peak at about 4.4° to 4.6° (hereinafter, “peak D”)

a characteristic peak at about 4.1° to 4.3° (hereinafter, “peak E”), and

a characteristic peak at about 3.7° to 3.9° (hereinafter, “peak F”).

Peak C comprises characteristic peaks at about 4.70 to 4.9° and/or about4.9° to 5.0°.

The crystal of 2ccPA of the present invention is substantially in alaminated flaky crystalline form.

The crystal of 2ccPA of the present invention has a melting point withinthe range of 187° C. to 190° C. The melting point is measured with amelting point measuring apparatus B-545 (produced by Büchii).

The IR spectrum of the crystal of 2ccPA of the present invention ismeasured with a Spectrum One B IR spectrometer (Perkin Elmer).

The purity of the crystal of 2ccPA of the present invention is measuredwith high-performance liquid chromatography (HPLC) using a reverse-phasesilica gel column. The purity is typically 98% or more.

The crystal of 2ccPA of the present invention is excellent in storagestability. After being hermetically sealed and stored at −20° C. and 35°C. for 3 months, the crystal of 2ccPA shows little decrease in purityand does not significantly decompose.

2. Method for Producing Crystal of 2ccPA

The method for producing the crystal of 2ccPA of the present inventioncomprises the following step (H) and step (I).

The method comprises:

step (H) of reacting a cyclic phosphonic acid ester represented byformula (9):

wherein R¹ is as defined above with a sodium halide in an organicsolvent to obtain 2ccPA, and

step (I) of concentrating a solution containing the 2ccPA obtained instep (H) under reduced pressure or cooling the solution containing the2ccPA obtained in step (H) to precipitate the crystal.

The method for producing the crystal of 2ccPA of the present inventionmay further comprise, in addition to step (H) and step (I), thefollowing step (J) and step (K):

step (J) of dissolving the crystal obtained in step (H) and step (I) inwater and/or an organic solvent; and

step (K) of adding a poor solvent to the solution obtained in step (J)to perform recrystallization.

2-1. Step (H)

Step (H) is illustrated in the following reaction scheme-2:

wherein R¹ is as defined above.

Specifically, step (H) is a step of reacting the cyclic phosphonic acidester represented by formula (9) with a sodium halide in an organicsolvent to obtain 2ccPA represented by formula (1), and step (H)produces a solution containing 2ccPA.

The cyclic phosphonic acid ester represented by formula (9) and used instep (H) is produced through the production steps described later.

In the cyclic phosphonic acid ester represented by formula (9), examplesof the alkyl represented by R¹ include linear or branched alkyl having 1to 10 carbon atoms. Specific examples include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, and n-nonyl. The alkyl represented by R: ispreferably alkyl having 1 to 6 carbon atoms, more preferably alkylhaving 1 to 4 carbon atoms, and particularly preferably methyl, ethyl,and isopropyl.

The alkyl may contain 1 to 5 substituents, and preferably 1 to 3substituents, such as halogen atoms (e.g., fluorine, chlorine, andbromine), alkoxy having 1 to 6 carbon atoms, and nitro.

Examples of the arylalkyl represented by R¹ include arylalkyl having 7to 16 carbon atoms (the aryl moiety has 6 to 10 carbon atoms, and thealkyl moiety has 1 to 6 carbon atoms). Specific examples include benzyl;1-phenyl ethyl, 2-phenyl ethyl; 1-phenyl propyl, 2-phenyl propyl,3-phenyl propyl; 1-phenyl butyl, 2-phenyl butyl, 3-phenyl butyl,4-phenyl butyl; and naphthyl methyl. The arylalkyl represented by R¹ ispreferably arylalkyl having 7 to 11 carbon atoms, more preferablyarylalkyl having 7 or 8 carbon atoms, and particularly preferablybenzyl.

The aryl constituting the arylalkyl represented by R¹ may contain 1 to 5substituents, and preferably 1 to 3 substituents, such as halogen atoms(e.g., fluorine, chlorine, and bromine), alkyl having 1 to 6 carbonatoms, alkoxy having 1 to 6 carbon atoms, and nitro.

Examples of the aryl represented by R¹ include monocyclic, dicyclic, ormore than dicyclic aryl. Specific examples of the aryl include phenyl,naphthyl, anthryl, and phenanthryl. Of these, substituted orunsubstituted phenyl is preferable. The aryl may contain 1 to 5substituents, and preferably 1 to 3 substituents, such as halogen atoms(e.g., fluorine, chlorine, and bromine), alkyl having 1 to 6 carbonatoms, alkoxy having 1 to 6 carbon atoms, and nitro.

The sodium halide for use in step (H) may be of a wide range of knownsodium halides, such as sodium fluoride, sodium chloride, sodiumbromide, and sodium iodide. Of these, sodium iodide is preferable. Thesesodium halides may be used singly or in a combination of two or more.

The amount of the sodium halide for use is typically 1 to 5 moles,preferably 1 to 3 moles, and more preferably 1 to 1.5 moles, per mole ofthe compound represented by formula (9).

The organic solvent for use in step (H) is not particularly limited, aslong as the solvent does not adversely affect the reaction. Examples ofthe organic solvent for use include ketone solvents (e.g., branched orlinear ketone and cyclic ketone, such as acetone, methyl ethyl ketone,methyl butyl ketone, methyl isobutyl ketone, DIBK (diisobutyl ketone),and cyclohexanone), alcohol solvents (e.g., methanol and ethanol), ethersolvents (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran (THF),and 1,4-dioxane), aromatic hydrocarbon solvents (e.g., benzene, toluene,and xylene), aliphatic or alicyclic hydrocarbon solvents (e.g.,n-pentane, n-hexane, cyclohexane, and petroleum ether), ester solvents(e.g., ethyl acetate), and halogenated hydrocarbon solvents (e.g.,methylene chloride, chloroform, and 1,2-dichloroethylene). These organicsolvents may be used singly or in a combination of two or more. Of theseorganic solvents, ketone solvents are preferable, with acetone, methylethyl ketone, and methyl isobutyl ketone being particularly preferable.

The amount of the organic solvent for use can be suitably selected froma wide range. For example, the amount of the organic solvent istypically 2 to 20 liters, and preferably 2 to 5 liters, per mole of thecompound represented by formula (9).

Step (H) may be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically 0 to 120° C., preferably 50 to120° C., and more preferably 70 to 120° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 1 to 24 hours.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the sodium halide), the unreactedstarting material compound, and other components are removed by atypical separation technique, such as concentration, crystallization,and filtration to isolate the target 2ccPA represented by formula (1).

2-2. Step (I)

Step (I) is a step of concentrating a solution containing the 2ccPAobtained in step (H) under reduced pressure, or cooling the solutioncontaining the 2ccPA obtained in step (H) to precipitate the crystal.

The reduced pressure in step (I) is not particularly limited, as long asthe crystal can be precipitated under the pressure. The reduced pressureis typically lower than the atmospheric pressure.

The cooling temperature in step (I) is not particularly limited, as longas the crystal can be precipitated at the temperature. The coolingtemperature is typically lower than the temperature of the solutionafter the reaction in step (H), and preferably 0 to 30° C., and morepreferably 10 to 25° C.

The cooling time is not particularly limited, and typically 0.1 to 100hours, preferably 0.5 to 50 hours, and more preferably 1 to 2 hours.

The obtained crystal can be used in the subsequent step (J).

2-3. Step (J)

Step (J) is a step of dissolving the crystal obtained in step (H) andstep (I) in water and/or an organic solvent to obtain a solution.

The water and/or organic solvent for use in step (J) can be any waterand/or organic solvent that can dissolve the crystal obtained in step(I). Examples of the organic solvent include alcohol solvents, and inparticular, methanol, ethanol, 1-propanol, isopropyl alcohol, and1-butanol are preferable.

The amount of the water and/or organic solvent for use can be suitablyselected from a wide range. For example, the amount of the water and/ororganic solvent is typically 0.5 to 20 liters, and preferably 0.5 to 2liters, per mole of 2ccPA.

In the use of a mixture solvent of water and an organic solvent, themixing ratio is not particularly limited. The mixing ratio of water toan organic solvent is preferably 1:99 to 99:1, and more preferably 30:70to 70:30.

The temperature at which the crystal is dissolved is not particularlylimited, and is typically 0 to 100° C., preferably 10 to 80° C., andmore preferably 20 to 60° C.

The time period for step (J) is not particularly limited, and istypically 0.1 to 100 hours, preferably 0.5 to 50 hours, and morepreferably 1 to 2 hours.

2-4. Step (K)

Step (K) is a step of adding a poor solvent to the solution obtained instep (J) to perform recrystallization.

The poor solvent for use in step (K) may be any solvent that canprecipitate a crystal from the solution obtained in step (J).Specifically, the poor solvent can be any solvent that is poorer thanthe solvent used in step (J) (good solvent). Examples of poor solventsinclude ketone solvents (e.g., acetone, methyl ethyl ketone, and methylisobutyl ketone), ether solvents (e.g., diethyl ether, diisopropylether, tetrahydrofuran (THF), and 1,4-dioxane), aromatic hydrocarbonsolvents (e.g., benzene, toluene, and xylene), aliphatic or alicyclichydrocarbon solvents (e.g., n-pentane, n-hexane, cyclohexane, andpetroleum ether), ester solvents (e.g., methyl acetate, ethyl acetate,isopropyl acetate, and butyl acetate), halogenated hydrocarbon solvents(e.g., methylene chloride, chloroform, and 1,2-dichloroethylene), andalcohol solvents having 3 or more carbon atoms (e.g., 1-propanol).

The solvent for use in step (K) may be any solvent that is poorer thanthe solvent used in step (J) (good solvent). For example, if the solventused in step (K) is methanol, an alcohol solvent having 3 or more carbonatoms (e.g., 1-propanol) can be used as a poor solvent. The organicsolvents may be used singly or in a combination of two or more. Of theseorganic solvents, ketone solvents are preferable, and in particular,acetone, methyl ethyl ketone, and methyl isobutyl ketone are preferable.

The amount of the poor solvent for use can be suitably selected from awide range. For example, the amount of the poor solvent is typically 1to 30 liters, and preferably 2 to 5 liters, per mole of 2ccPA.

The temperature at which the poor solvent is added is typically −20° C.to 30° C., preferably −10° C. to 20° C., and more preferably 0° C. to20° C.

The crystal of the cyclic phosphonic acid sodium salt (2ccPA) obtainedby the production method comprising step (H) and step (I) or theproduction method comprising step (H) to step (K) has advantages in itshigh purity and excellent storage stability.

3. Method for Producing Cyclic Phosphonic Acid Ester Represented byFormula (9)

The cyclic phosphonic acid ester represented by formula (9) of thepresent invention is produced through the steps illustrated in thefollowing reaction scheme-3:

wherein R¹, R², R³, and X are as defined above.

The following describes step (A) to step (G) in detail.

3-1. Step (A): Acetal Protection Step

Step (A) is illustrated in the following reaction scheme-4:

wherein R² is as defined above.

Specifically, step (A) is a step of reacting2-hydroxymethyl-1,3-propanediol represented by formula (2) with a ketonecompound or acetal compound in the presence of an acid to produce acyclic acetal compound represented by formula (3) (acetal protectionstep).

The ketone compound for use in step (A) is not particularly limited, aslong as the ketone compound is an organic compound having the ketogroup. Examples of the ketone compounds include a ketone compoundrepresented by formula (10):

wherein R² is as defined above; and two R² groups may be bonded togetherto form alkylene, and the alkylene may be further substituted orunsubstituted.

The acetal compound for use in step (A) is not particularly limited.Examples include an acetal compound represented by the following formula(11):

wherein R² is as defined above; two R² groups may be bonded together toform alkylene, and the alkylene may be further substituted orunsubstituted; and two R⁴ groups are the same or different and representalkyl.

In the ketone compound represented by formula (10) or the acetalcompound represented by formula (11), the alkyl represented by R² is,for example, linear or branched alkyl having 1 to 10 carbon atoms.Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, andn-nonyl. The alkyl is preferably alkyl having 1 to 6 carbon atoms, morepreferably alkyl having 1 to 4 carbon atoms, and particularly preferablymethyl, ethyl, and isopropyl. The alkyl may contain 1 to 5 substituents,and preferably 1 to 3 substituents, such as halogen atoms (e.g.,fluorine, chlorine, and bromine), aryl (e.g., phenyl and naphthyl), andcarboxyl.

In the ketone compound represented by formula (10) or the acetalcompound represented by formula (11), the cycloalkyl of the cycloalkylthat may be substituted or unsubstituted and represented by R² may be,for example, cycloalkyl having 3 to 10 carbon atoms. Specific examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. The cycloalkyl is preferably cycloalkyl having 3 to 7carbon atoms, more preferably cycloalkyl having 5 to 7 carbon atoms, andparticularly preferably cyclohexyl. The cycloalkyl may contain 1 to 5substituents, and preferably 1 to 3 substituents, such as halogen atoms(e.g., fluorine, chlorine, and bromine), alkyl (alkyl having 1 to 6carbon atoms), aryl (e.g., phenyl and naphthyl), and carboxyl.

In the ketone compound represented by formula (10) or the acetalcompound represented by formula (11), the aryl of the aryl that may besubstituted or unsubstituted and represented by R² may be, for example,monocyclic, dicyclic, or more than dicyclic aryl. Specific examplesinclude phenyl, naphthyl, anthryl, and phenanthryl. Of these,substituted or unsubstituted phenyl is preferable. The aryl may contain1 to 5 substituents, and preferably 1 to 3 substituents, such as halogenatoms (e.g., fluorine, chlorine, and bromine), alkyl (alkyl having 1 to6 carbon atoms), and carboxyl.

In formula (10) or (11), two R groups may be bonded together to formalkylene, and the alkylene may be substituted or unsubstituted. When twoR² groups are bonded together to form alkylene, the alkylene is, forexample, —(CH₂)_(q)— wherein q is an integer of 1 to 6, —(CH═CH)_(r)—wherein r represents 1, 2 or 3, or —CH═CH—(CH₂)_(s)— wherein srepresents 1, 2 or 3.

The alkylene may be substituted or unsubstituted, and examples of thesubstituents include alkyl (e.g., alkyl having 1 to 6 carbon atoms),aryl (e.g., phenyl and naphthyl), oxo (═O), and halogen atoms (e.g.,fluorine, chlorine, bromine, and iodine). A divalent hydrocarbon groupmay contain 1 to 5 substituents selected from the group consisting ofthese substituents.

In the acetal compound represented by formula (11), the alkylrepresented by R⁴ is, for example, linear or branched alkyl having 1 to10 carbon atoms. Specific examples include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, and n-nonyl. The alkyl is preferably alkyl having 1to 6 carbon atoms, more preferably alkyl having 1 to 4 carbon atoms, andparticularly preferably methyl, ethyl, and isopropyl. The alkyl maycontain 1 to 5 substituents, and preferably 1 to 3 substituents, such ashalogen atoms (e.g., fluorine, chlorine, and bromine), aryl (e.g.,phenyl and naphthyl), and carboxyl.

Specific examples of the ketone compound for use in step (A) includelinear aliphatic ketone compounds having 3 to 20 carbon atoms, such asacetone, 2-butanone (methyl ethyl ketone), 2-pentanone, 3-pentanone,4-methyl-2-pentanone, methyl isopropyl ketone, methyl isobutyl ketone,2-hexanone, 3-hexanone, 2-heptanone, 3-heptanone, 2-octanone,3-octanone, 2-nonanone, 2-decanone, 4-decanone, 2-undecanone, and6-undecanone; alicyclic ketone compounds having 6 to 20 carbon atoms,such as 2-methylcyclohexanone, 3-methylcyclohexanone, 3-methylcyclopentanone, and 4-acetyl-1-methylcyclohexene; aromatic ketonecompounds having 6 to 20 carbon atoms, such as acetophenone,1-(4-chlorophenyl)-1-ethanone, 1-(2-chlorophenyl)-1-ethanone,1-(4-fluorophenyl)-1-ethanone, 1-(2-fluorophenyl)-1-ethanone,1-(4-methylphenyl)-1-ethanone, 1-(2-methylphenyl)-1-ethanone,1-(4-nitrophenyl)-1-ethanone, 1-(4-tert-butylphenyl)-1-ethanone,1-(4-methoxyphenyl)-1-ethanone, 1-(4-allyloxycarbonylphenyl)-1-ethanone, 1-phenyl-2-propanone, methyl4-oxo-4-phenylbutanoate, ethyl 4-oxo-4-phenylbutanoate,1-phenyl-2-butanone, 4-phenyl-2-butanone, 2-phenylcyclopentanone,2-phenylcycloheptanone, 9-acetylanthracene, 2-acetylbiphenyl,4-acetylbiphenyl, 2-acetylnaphthalene, 2-acetylphenanthrene,3-acetylphenanthrene, and 9-acetylphenanthrene; and aralkyl ketonecompounds, such as 2-acetyl-5-norbornene.

Of these compounds, acetone, 2-pentanone, 3-pentanone, methyl ethylketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclobutanone,cyclopentanone, and cyclohexanone are preferable. Acetone, methyl ethylketone, and methyl isobutyl ketone are particularly preferable.

Specific examples of the acetal compound for use in the presentinvention include 2,2-dimethoxypropane, 2,2-diethoxypropane,2,2-dipropoxypropane, 2,2-dibutoxypropane, 1,1-dimethoxycyclohexane,1,1-dimethylcyclopentane, benzophenone dimethyl acetal,2,2-dimethyl-1,3-dioxolane, 4,4-dimethoxyheptane, 5,5-dimethoxynonane,4,4-diethoxyheptane, and 5,5-diethoxynonane. Particularly preferable are2,2-dimethoxypropane, 2,2-dipropoxypropane, 2,2-dibutoxypropane, andbenzophenone dimethyl acetal.

The acid for use in step (A) includes known inorganic acids and organicacids. Examples of the inorganic acids include hydrochloric acid andsulfuric acid. Examples of the organic acids include sulfonic acidcompounds, such as methanesulfonic acid, trifluoromethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, and pyridiniump-toluenesulfonate; and carboxylic acid compounds, such as acetic acid.In particular, as the acid, hydrochloric acid, sulfuric acid,p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and acetic acidare preferable. If acetic acid is used, acetic acid can also be used asa solvent.

The amount of the acid for use can be suitably selected from a widerange. For example, the amount of the acid is typically 0.01 to 500moles, preferably 0.01 to 2 moles, and more preferably 0.01 to 1 mole,per mole of 2-hydroxymethyl-1,3-propanediol represented by formula (2).

Step (A) is performed in the presence or absence of a solvent. When asolvent is used, the solvent is not particularly limited, as long as thesolvent does not adversely affect the reaction. Examples of the solventfor use include alcohol solvents (e.g., methanol and ethanol), ethersolvents (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran (THF),and 1,4-dioxane), aromatic hydrocarbon solvents (e.g., benzene, toluene,and xylene), aliphatic or alicyclic hydrocarbon solvents (e.g.,n-pentane, n-hexane, cyclohexane, and petroleum ether), ester solvents(e.g., ethyl acetate), and halogenated hydrocarbon solvents (e.g.,methylene chloride, chloroform, and 1,2-dichloroethylene). Thesesolvents may be used singly or in a combination of two or more. Of thesesolvents, methanol, THF, 1,4-dioxane, and toluene are preferable, andTHF is particularly preferable.

The amount of the solvent for use can be suitably selected from a widerange. For example, the amount of the solvent is typically 0 to 20liters, and preferably 0 to 5 liters, per mole of the compoundrepresented by formula (2).

Step (A) can be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically 0 to 100° C., preferably 10 to 80°C., and more preferably 20 to 80° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 1 to 10 hours.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the ketone compound), the unreactedstarting material compound, and other components are removed by atypical separation technique, such as liquid separation, distillation,and column purification to isolate the target cyclic acetal compoundrepresented by formula (3). Alternatively, after completion of thereaction, only concentration may be performed, and the mixture obtainedafter reaction may be used as it is in step (B) without performingpurification and isolation steps (Telescoping synthesis).

3-2. Step (B): Sulfonylation Step

Step (B) is illustrated in the following reaction scheme-5:

wherein R² and R³ are as defined above.

Step (B) is a step of reacting the compound represented by formula (3)with a sulfonyl halide compound to obtain the compound represented byformula (4) (sulfonylation step).

For example, step (B) allows the alcohol compound represented by formula(3) to react with a sulfonyl halide compound in an organic solvent inthe presence of a base to obtain the sulfonate compound represented byformula (4). For example, to perform the reaction using mesyl chlorideas the sulfonyl compound, the method disclosed in Non-patent Literature2 can be referred to.

Examples of the sulfonyl halide compound for use in step (B) includealkyl sulfonyl halide, such as methyl sulfonyl chloride, methyl sulfonylbromide, and methyl sulfonyl iodide; and aryl sulfonyl halide, such asphenyl sulfonyl chloride and tosyl chloride.

The amount of the sulfonyl halide compound for use can be suitablyselected from a wide range. For example, the amount of the sulfonylhalide compound is typically 1 to 500 moles, preferably 1 to 10 moles,and more preferably 1 to 2 moles, per mole of the methanol compoundrepresented by formula (3).

Step (B) is performed in the presence or absence of a solvent. When asolvent is used, the solvent is not particularly limited, as long as thesolvent does not adversely affect the reaction. Examples of the solventfor use include alcohol solvents (e.g., methanol and ethanol), ethersolvents (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran (THF),and 1,4-dioxane), aromatic hydrocarbon solvents (e.g., benzene, toluene,and xylene), aliphatic or alicyclic hydrocarbon solvents (e.g.,n-pentane, n-hexane, cyclohexane, and petroleum ether), ester solvents(e.g., ethyl acetate), halogenated hydrocarbon solvents (e.g., methylenechloride (MDC, DCM), chloroform, and 1,2-dichloroethylene). Thesesolvents may be used singly or in a combination of two or more. Of thesesolvents, THF, 1,4-dioxane, toluene, and methylene chloride arepreferable, and methylene chloride is particularly preferable.

The amount of the solvent for use can be suitably selected from a widerange. For example, the amount of the solvent is typically 0 to 20liters, and preferably 1 to 5 liters, per mole of the compoundrepresented by formula (2).

Step (B) can be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically −40 to 100° C., preferably −30 to80° C., and more preferably −20 to 20° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 1 to 4 hours.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the sulfonyl halide compound), theunreacted starting material compound, and other components are removedby a typical separation technique, such as liquid separation,concentration, and column purification to isolate the target cyclicacetal compound represented by formula (4). Alternatively, aftercompletion of the reaction, only liquid separation and concentration maybe performed, and the mixture obtained after reaction may be used as itis in step (C) without performing purification and isolation steps(Telescoping synthesis).

3-3. Step (C): Halogenation Step

Step (C) is illustrated in the following reaction scheme-6:

wherein R², R³, and X are as defined above.

Specifically, step (C) is a step of reacting the compound represented byformula (4) with an alkali metal halide and/or an alkaline-earth metalhalide in the presence of a base to obtain the compound represented byformula (5) (halogenation step).

The alkali metal halide for use in step (C) is not particularly limited.Examples include lithium halides (e.g., lithium fluoride, lithiumchloride, lithium bromide, and lithium iodide), sodium halides (e.g.,sodium fluoride, sodium chloride, sodium bromide, and sodium iodide),potassium halides (e.g., potassium fluoride, potassium chloride,potassium bromide, and potassium iodide), and cesium halides (e.g.,cesium fluoride, cesium chloride, cesium bromide, and cesium iodide). Ofthese, sodium iodide is preferable. These alkali metal halides may beused singly or in a combination of two or more.

The alkaline-earth metal halide for use in step (C) is not particularlylimited. Examples include magnesium halides (e.g., magnesium fluoride,magnesium chloride, magnesium bromide, and magnesium iodide), calciumhalides (e.g., calcium fluoride, calcium chloride, calcium bromide, andcalcium iodide), strontium halides (e.g., strontium fluoride, strontiumchloride, strontium bromide, and strontium iodide), and barium halides(e.g., barium fluoride, barium chloride, barium bromide, and bariumiodide). These alkaline-earth metal halides may be used singly or in acombination of two or more.

The amount of the alkali metal halide and/or alkaline-earth metal halidefor use is typically 1 mole or more, preferably 1 to 10 moles, and morepreferably 1 to 3 moles, per mole of the compound represented by formula(4).

Examples of the base for use in step (C) include organic bases andinorganic bases.

Examples of the organic bases include organic amines containing 1 to 3,preferably 3 alkyl groups having 1 to 4 carbon atoms, such astrimethylamine, triethylamine, tributylamine, and diisopropylethylamine.In particular, triethylamine is preferable.

Specific examples of the inorganic bases include carbonates of alkalimetals or alkaline-earth metals, such as sodium hydrogen carbonate,sodium carbonate, potassium hydrogen carbonate, potassium carbonate, andcalcium carbonate. In particular, sodium hydrogen carbonate ispreferable.

The amount of the base for use may be the catalytic amount. For example,the amount of the base is typically 0.01 moles or more, preferably 0.01to 1 mole, and more preferably 0.05 to 0.5 moles, per mole of thesulfonate compound represented by formula (4).

In step (C), adding a catalytic amount of a base prevents decompositionto thereby produce the halogen compound represented by formula (5) at ahigh yield.

Step (C) is performed in the presence or absence of a solvent. When asolvent is used, the solvent is not particularly limited, as long as thesolvent does not adversely affect the reaction. Examples of the solventfor use include ketone solvents (e.g., acetone, methyl ethyl ketone, andmethyl isobutyl ketone), alcohol solvents (e.g., methanol and ethanol),ether solvents (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran(THF), and 1,4-dioxane), aromatic hydrocarbon solvents (e.g., benzene,toluene, and xylene), aliphatic or alicyclic hydrocarbon solvents (e.g.,n-pentane, n-hexane, cyclohexane, and petroleum ether), ester solvents(e.g., ethyl acetate), and halogenated hydrocarbon solvents (e.g.,methylene chloride, chloroform, and 1,2-dichloroethylene). Thesesolvents may be used singly or in a combination of two or more. Of thesesolvents, acetone, methyl ethyl ketone, and methyl isobutyl ketone areparticularly preferable.

The amount of the solvent for use can be suitably selected from a widerange. For example, the amount of the solvent is typically 0 to 20liters, and preferably 1 to 5 liters, per mole of the compoundrepresented by formula (4).

Step (C) can be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically 0 to 120° C., preferably 10 to100° C., and more preferably 55 to 80° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 1 to 18 hours.

This reaction is a novel reaction that uses a base in halogenation.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the alkali metal halide,alkaline-earth metal, and base), the unreacted starting materialcompound, and other components are removed by a typical separationtechnique, such as liquid separation, concentration, and columnpurification to isolate the target compound represented by formula (5).Alternatively, after completion of the reaction, the mixture obtainedafter reaction may be used as it is in step (D) without performingpurification and isolation steps (Telescoping synthesis).

3-4. Step (B′): Another Halogenation Step

Step (B′) is illustrated in the following reaction scheme-7:

wherein R and X are as defined above.

Specifically, step (B′) is a step of reacting the cyclic acetal compoundrepresented by formula (3) with a halogenating agent.

The halogenating agent for use in step (B′) is not particularly limited.Examples of the halogenating agent for chlorination include chlorine,thionyl chloride, phosphorus trichloride, phosphorus pentachloride,triphenylphosphine-carbon tetrachloride, andtriphenylphosphine-N-chlorosuccinimide. Examples of the halogenatingagent for bromination include bromine, hydrobromic acid, phosphorustribromide, triphenylphosphine-bromine,triphenylphosphine-N-bromosuccinimide, triphenylphosphine-carbontetrabromide, and thionyl bromide. Examples of the halogenating agentfor iodination include iodine, triphenylphosphine-iodine, andtriphenylphosphine-N-iodosuccinimide. Of these,triphenylphosphine-iodine and triphenylphosphine-carbon tetrabromide arepreferable.

The amount of the halogenating agent for use is typically 1 to 500moles, preferably 1 to 10 moles, and more preferably 1 to 2 moles, permole of the alcohol compound represented by formula (3).

The reaction of step (B′) can be performed in the presence of imidazoleto scavenge the acid generated in the reaction.

The amount of imidazole for use is typically 1 to 500 moles, preferably1 to 10 moles, and more preferably 1 to 2 moles, per mole of the cyclicacetal compound represented by formula (3).

Step (B′) is performed in the presence or absence of a solvent. When asolvent is used, the solvent is not particularly limited, as long as thesolvent does not adversely affect the reaction. Examples of the solventfor use include ketone solvents (e.g., acetone, methyl ethyl ketone, andmethyl isobutyl ketone), alcohol solvents (e.g., methanol and ethanol),ether solvents (e.g., diethyl ether, diisopropyl ether, cyclopentylmethyl ether (CPME), tetrahydrofuran (THF), and 1,4-dioxane), aromatichydrocarbon solvents (e.g., benzene, toluene, and xylene), aliphatic oralicyclic hydrocarbon solvents (e.g., n-pentane, n-hexane, cyclohexane,and petroleum ether), ester solvents (e.g., ethyl acetate), andhalogenated hydrocarbon solvents (e.g., methylene chloride, chloroform,and 1,2-dichloroethylene). These solvents may be used singly or in acombination of two or more. Of these solvents, acetone, methyl ethylketone, and methyl isobutyl ketone are particularly preferable.

The amount of the solvent for use can be suitably selected from a widerange. For example, the amount of the solvent is typically 0 to 20liters, and preferably 1 to 5 liters, per mole of the compoundrepresented by formula (4).

Step (B′) can be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically 0 to 100° C., preferably 0 to 40°C., and more preferably 0 to 20° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 1 to 5 hours.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the halogenating agent), theunreacted starting material compound, and other components are removedby a typical separation technique, such as liquid separation,concentration, and column purification to isolate the target compoundrepresented by formula (5). Alternatively, after completion of thereaction, the mixture obtained after reaction may be used as it is instep (D) without performing purification and isolation steps(Telescoping synthesis).

3-5. Step (D): Phosphonate Diesterification Step

Step (D) is illustrated in the following reaction scheme-8:

wherein R¹, R², and X are as defined above.

Specifically, step (D) is a step of reacting the compound represented byformula (5) with a phosphorous acid diester in the presence of a base toobtain the compound represented by formula (6) (phosphonatediesterification step).

Examples of the phosphorous acid diester for use in step (D) include acompound represented by the following formula (12):

wherein R¹ is as defined above.

In the phosphorous acid diester represented by formula (12), alkyl,arylalkyl, or aryl represented by R¹ is the same as alkyl, arylalkyl, oraryl represented by R¹ in the cyclic phosphonic acid ester representedby formula (9).

Specific examples of phosphorous acid diester include dialkyl phosphite,such as dimethyl phosphite, diethyl phosphite, dipropyl phosphite,dibutyl phosphite, diisopropyl phosphite, and methylethyl phosphite;diarylalkyl phosphite, such as dibenzyl phosphite, and di(phenylethyl)phosphite; and diaryl phosphite, such as diphenyl phosphite, and ditolylphosphite. Preferable are dimethyl phosphite, diethyl phosphite,dibenzyl phosphite, and diphenyl phosphite.

The amount of the phosphorous acid diester for use is not particularlylimited. For example, the amount is preferably 1 to 10 equivalents, andparticularly preferably 2 to 2.5 equivalents, per equivalent of thehalogen compound represented by formula (5).

The solvent for use in step (D) is not particularly limited, as long asthe solvent is an organic solvent. For example, an aprotic polar solventcan be used. Examples of the aprotic polar solvent include amidesolvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMAc), N-methylpyrrolidone (NMP), and 1,3-dimethyl-2-imidazolidinone;dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA),acetonitrile (AN), acetone, and THF. DMF, DMAc, and acetonitrile areparticularly preferable. These solvents may be used singly or in acombination of two or more.

The amount of the solvent for use can be suitably selected from a widerange. For example, the amount of the solvent is typically 0 to 20liters, and preferably 1 to 5 liters, per mole of the compoundrepresented by formula (5).

Examples of the base for use in step (D) include organic bases andinorganic bases.

Examples of the organic bases include organic amines containing 1 to 3,preferably 3 alkyl groups having 1 to 4 carbon atoms, such astrimethylamine, triethylamine, tributylamine, and diisopropylethylamine.Triethylamine is particularly preferable.

Specific examples of the inorganic bases include carbonates of alkalimetals or alkaline-earth metals, such as sodium hydrogen carbonate,sodium carbonate, potassium hydrogen carbonate, potassium carbonate,rubidium carbonate, calcium carbonate, and cesium carbonate. Cesiumcarbonate and rubidium carbonate are particularly preferable.

The amount of the base for use is not particularly limited. The amountis preferably 1 to 10 equivalents, and particularly preferably 2 to 2.5equivalents, per equivalent of the compound represented by formula (5).

Step (D) can be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically 0 to 120° C., preferably 20 to 80°C., and more preferably 40 to 50° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 5 to 8 hours.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the phosphorous acid diester andbase), the unreacted starting material compound, and other componentsare removed by a typical separation technique, such as concentration,filtration, and column purification to isolate the target compoundrepresented by formula (6). Alternatively, after completion of thereaction, only concentration and filtration may be performed, and themixture obtained after reaction may be used as it is in step (E) withoutperforming purification and isolation steps (Telescoping synthesis).

3-6. Step (E): Ring-Opening Step

Step (E) is illustrated in the following reaction scheme-9:

wherein R¹ and R are as defined above.

Specifically, step (E) is a step of allowing an acid to act on thecompound represented by formula (6) to obtain the compound representedby formula (7) (ring-opening step).

Any known organic acids or inorganic acids can be used as the acid.Examples of the organic acids include sulfonic acids, such asp-toluenesulfonic acid (p-TsOH), pyridinium p-toluenesulfonate (PPTS),and camphorsulfonic acid (CSA); and lower fatty acids having 1 to 4carbon atoms, such as formic acid, acetic acid, propionic acid, butyricacid, and trifluoroacetic acid (TFA). p-TsOH and CSA are particularlypreferable.

Specific examples of the inorganic acids include hydrochloric acid,sulfuric acid, and nitric acid. Hydrochloric acid is particularlypreferable.

The amount of the acid for use is not particularly limited. The amountis preferably 0.01 to 0.2 moles, and particularly preferably 0.01 to 0.1moles, per mole of the compound represented by formula (6).

Step (E) is performed in the presence or absence of a solvent. When asolvent is used, the solvent is not particularly limited, as long as thesolvent does not adversely affect the reaction. Examples of the solventfor use include water, alcohol solvents (e.g., lower alcohols having 1to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol,and n-butanol), ether solvents (e.g., diethyl ether, diisopropyl ether,tetrahydrofuran (THF), and 1,4-dioxane), aromatic hydrocarbon solvents(e.g., benzene, toluene, and xylene), aliphatic or alicyclic hydrocarbonsolvents (e.g., n-pentane, n-hexane, cyclohexane, and petroleum ether),ester solvents (e.g., ethyl acetate), halogenated hydrocarbon solvents(e.g., methylene chloride, chloroform, and 1,2-dichloroethylene). Thesesolvents may be used singly or in a combination of two or more. Of thesesolvents, methanol, THF, 1,4-dioxane, and toluene are preferable, andmethanol is particularly preferable.

The amount of the solvent for use can be suitably selected from a widerange. For example, the amount of the solvent is typically 0 to 20liters, and preferably 1 to 5 liters, per mole of the compoundrepresented by formula (6).

Step (E) can be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically 0 to 120° C., preferably 0 to 80°C., and more preferably 0 to 20° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 3 to 12 hours.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the acid), the unreacted startingmaterial compound, and other components are removed by a typicalseparation technique, such as concentration and column purification toisolate the target compound represented by formula (7). Alternatively,after completion of the reaction, only concentration may be performed,and the mixture obtained after reaction may be used as it is in step (F)without performing purification and isolation steps (Telescopingsynthesis).

3-7. Step (F): Cyclization Step

Step (F) is illustrated in the following reaction scheme-10:

wherein R¹ is as defined above.

Specifically, step (F) is a step of allowing a base to act on thecompound represented by formula (7) to obtain the compound of formula(8) (cyclization step).

Any known organic bases or inorganic bases can be used as the base foruse in step (F). Examples of the organic bases include tertiary organicamines, such as diazabicycloundecene (DBU), diazabicyclononene (DBN),trimethylamine, triethylamine (TEA), tributylamine, anddiisopropylethylamine (DIPEA); and metal alkoxides, such as sodiummethoxide (NaOMe), sodium ethoxide (NaOEt), potassium t-butoxide(t-BuOK), and sodium t-butoxide (t-BuONa).

Examples of the inorganic bases include alkali metal carbonates, such ascesium carbonate (Cs₂CO₃), and rubidium carbonate (Rb₂CO₃); and alkalimetal hydrides, such as sodium hydride (NaH).

The base is preferably DBU, DBN, TEA, DIPEA, NaOMe, NaOEt, t-BuOK,t-BuONa, Cs₂CO₃, and NaH, and more preferably DBU and DBN.

The amount of the base for use is not particularly limited. For example,the amount of the base is preferably 0.1 to 2 moles, and particularlypreferably 0.1 to 1 mole, per mole of the compound represented byformula (7).

Step (F) is performed in the presence or absence of a solvent. When asolvent is used, the solvent is not particularly limited, as long as thesolvent does not adversely affect the reaction. Examples of the solventfor use include water, alcohol solvents (e.g., lower alcohols having 1to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol,and n-butanol); ether solvents (e.g., diethyl ether, diisopropyl ether(IPA), tetrahydrofuran (THF), and 1,4-dioxane); aromatic hydrocarbonsolvents (e.g., benzene, toluene, and xylene); aliphatic or alicyclichydrocarbon solvents (e.g., n-pentane, n-hexane, cyclohexane, andpetroleum ether); ester solvents (e.g., ethyl acetate); halogenatedhydrocarbon solvents (e.g., methylene chloride, chloroform, and1,2-dichloroethylene); amide solvents (e.g., N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), and1,3-dimethyl-2-imidazolidinone); dimethyl sulfoxide (DMSO);hexamethylphosphoric triamide (HMPA); acetonitrile (AN); and acetone.These solvents may be used singly or in a combination of two or more. Ofthese solvents, DMF, DMAc, AN, acetone, methanol, IPA, and butanol arepreferable, and DMF and DMAc are particularly preferable.

The amount of the solvent for use can be suitably selected from a widerange. For example, the amount of the solvent is typically 0 to 20liters, and preferably 1 to 5 liters, per mole of the compoundrepresented by formula (7).

In the reaction of step (F), a quenching agent may be used to terminatethe reaction. A known quenching agent, including, for example, anorganic acid, can be used as the quenching agent. Examples of theorganic acid include sulfonic acid, such as p-TsOH and CSA, and fattyacids having 1 to 4 carbon atoms, such as formic acid, acetic acid,propionic acid, butyric acid, and trifluoroacetic acid. p-TsOH and CSAare particularly preferable.

The amount of the quenching agent for use is preferably equimolar to theamount of the organic base added for the reaction.

Step (F) can be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically 0 to 60° C., preferably 0 to 40°C., and more preferably 15 to 25° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 2 to 7 hours.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the base), the unreacted startingmaterial compound, and other components are removed by a typicalseparation technique, such as concentration and column purification toisolate the target compound represented by formula (8). Alternatively,after completion of the reaction, only concentration may be performed,and the mixture obtained after reaction may be used as it is in step (G)without performing purification and isolation steps (Telescopingsynthesis).

3-8. Step (G): Esterification Step

Step (G) is illustrated in the following reaction scheme-11:

wherein R¹ is as defined above.

Specifically, step (G) is a step of reacting the cyclic phosphonic acidcompound represented by formula (8) with an oleic acid compound toobtain the compound of formula (9) (esterification step). A knownesterification reaction can be suitably applied.

Examples of the oleic acid compound include oleic acid and oleic acidderivatives, such as oleic acid halides, oleic anhydride, and oleic acidesters. These oleic acid compounds may be used singly or in acombination of two or more.

Examples of the halides of the oleic acid halides for use in step (G)include a chlorine atom, a bromine atom and an iodine atom. The halideis particularly preferably a chlorine atom.

Examples of the oleic acid esters for use in step (G) include methylester and ethyl ester.

The amount of the oleic acid compound for use is not particularlylimited. For example, the amount of the oleic acid compound ispreferably 1 to 2 moles, and particularly preferably 1 to 1.5 moles, permole of the compound represented by formula (8).

Examples of step (G) include:

a reaction of cyclic phosphonic acid compound (8) with an oleic acid inthe presence of a condensation agent (step G-1);

a reaction of cyclic phosphonic acid compound (8) with an oleic acidhalide in the presence of a base (step G-2);

a reaction of cyclic phosphonic acid compound (8) with an oleicanhydride (step G-3); and

a reaction of cyclic phosphonic acid compound (8) with an oleic acidester (step G-4).

Any known condensation agent can be used in step G-1 without limitation.Examples of the condensation agent include dicyclohexyl carbodiimide(DCC), diisopropyl carbodiimide (DIC), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC).

Examples of the base for use in step G-2 include organic bases, such astriethylamine, pyridine, N,N-diethylaniline, 4-dimethylaminopyridine,and diisopropylethylamine.

Examples of step (G-1) include the following step G-1A to step G-1F:

Step G-1A: a method comprising reacting cyclic phosphonic acid compound(8) with an oleic acid in the presence of the condensation agent;

Step G-1B: a method comprising reacting cyclic phosphonic acid compound(8) with an oleic acid in the presence of 2-chloro-1-methylpyridiniumiodide (CMPI);

Step G-1C: a method comprising reacting cyclic phosphonic acid compound(8) with an oleic acid in the presence of(benzotriazol-1-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate(pyBOP);

Step G-1D: a method comprising reacting cyclic phosphonic acid compound(8) with an oleic acid in the presence ofO-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (HATU);

Step G-1E: a method comprising reacting cyclic phosphonic acid compound(8) with an oleic acid in the presence ofO-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate(HBTU); and

Step G-1F: a method comprising reacting cyclic phosphonic acid compound(8) with an oleic acid in the presence of(l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino morpholinocarbenium hexafluorophosphate (COMU).

Examples of step (G-2) include the following step G-2A and step G-2B:

Step G-2A: a method comprising reacting cyclic phosphonic acid compound(8) with an oleic acid halide in the presence of triethylamine; and

Step G-2B: a method comprising producing an oleic acid halide from anoleic acid and reacting the oleic acid halide with cyclic phosphonicacid compound (8) in the presence of triethylamine.

Examples of step G-3 include the following step G-3A and step G-3B:

Step G-3A: a method comprising reacting cyclic phosphonic acid compound(8) with an oleic anhydride; and

Step G-3B: a method comprising reacting an oleic acid with tosylchloride to generate a mixed acid anhydride in the reaction system andreacting the acid anhydride with cyclic phosphonic acid compound (8).

The condensation agent or base is used in any amount within the range oftypically 0.25 moles to an excess amount, and preferably 0.5 to 2 moles,per mole of cyclic phosphonic acid compound (8). The condensation agentor base is suitably selected according to the type of oleic acidcompound or its derivative.

Step (G) can be performed in an inert gas atmosphere, such as nitrogenor argon.

The reaction pressure is not particularly limited, and the reaction canbe performed under ordinary pressure or increased pressure.

The reaction temperature is typically 0 to 120° C., preferably 0 to 30°C., and more preferably 15 to 25° C.

The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 50hours, and more preferably 2 to 17 hours.

After completion of the reaction, from the obtained reaction mixture, anexcess amount of the reagent (e.g., the oleic acid compound), theunreacted starting material compound, and other components are removedby a typical separation technique, such as liquid separation,concentration, and column purification to isolate the target compoundrepresented by formula (9). Alternatively, after completion of thereaction, only liquid separation and concentration may be performed, andthe mixture obtained after reaction may be used as it is in step (H)without performing purification and isolation steps (Telescopingsynthesis). The present invention is described in further detail withreference to Synthesis Examples, Examples, and Comparative Examples.However, the present invention is not limited to the following Examples.

Step (A) Synthesis Example A1: (Step A: R²=n-propyl) Synthesis of2,2-di-n-propyl-5-(hydroxymethyl)-1,3-dioxane (3b)

2-Hydroxymethyl-1,3-propanediol (2) (3.0 g) was dissolved in 30 mL oftetrahydrofuran, and 4.74 mL of 4-heptanone and 53.8 mg ofp-toluenesulfonic acid monohydrate were added thereto, followed byheating under reflux for 3.5 hours using a Dean-Stark trap. During thereaction, distilled tetrahydrofuran was discarded, and newtetrahydrofuran was added to the reaction mixture. Thereafter, 0.39 mLof triethylamine was added to the reaction mixture to stop the reaction,and tetrahydrofuran was distilled off under reduced pressure. Then, 30mL of ethyl acetate and 30 mL of water were added to the residue, andthe layers were separated. After the organic layer was extracted, thewater layer was further extracted twice with 30 mL of ethyl acetate. Thecombined organic layers were washed with 30 mL of saturated brine, driedover magnesium sulfate, and filtered, followed by distilling-off ofethyl acetate under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain2.34 g of acetal compound (3b) (yield: 41%).

¹H-NMR (500 MHz, CDCl₃):

δ: 0.93 (m, 6H), 1.35 (m, 4H), 1.63 (m, 3H), 1.72 (m, 2H), 1.79 (m, 1H),3.76 (m, 4H), 4.01 (dd, J=11.9, 4.0 Hz, 2H)

Synthesis Example A2 (Step A: R²=n-Butyl) Synthesis of2,2-dibutyl-5-(hydroxymethyl)-1,3-dioxane (3c)

2-Hydroxymethyl-1,3-propanediol (2) (1.0 g) was dissolved in 9.5 mL oftetrahydrofuran, and 1.96 mL of 5-nonanone and 17.9 mg ofp-toluenesulfonic acid monohydrate were added thereto, followed byheating under reflux for 17 hours. Thereafter, 0.13 mL of triethylaminewas added to the reaction mixture to stop the reaction, andtetrahydrofuran was distilled off under reduced pressure. Then, 10 mL ofethyl acetate and 10 mL of water were added to the residue, and thelayers were separated. After the organic layer was extracted, theaqueous layer was further extracted twice with 10 mL of ethyl acetate.The combined organic layers were washed with 10 mL of saturated brine,dried over magnesium sulfate, and filtered, followed by distilling-offof ethyl acetate under reduced pressure. The resulting residue waspurified with silica gel chromatography (n-hexane:ethyl acetate=1:1) toobtain 156 mg of acetal compound (3c) (yield: 7%).

¹H-NMR (500 MHz, CDCl₃):

δ: 0.92 (m, 6H), 1.31 (m, 8H), 1.50 (t, J=5.1 Hz, 1H), 1.65 (m, 2H),1.74 (m, 2H), 1.80 (m, 1H), 3.76 (m, 4H), 4.01 (dd, J=12.1, 4.1 Hz, 2H)

Synthesis Example A3 (Step A: R²=Phenyl) Synthesis of2,2-diphenyl-5-(hydroxymethyl)-1,3-dioxane (3d)

2-Hydroxymethyl-1,3-propanediol (2) (1.0 g) was dissolved in 48 mL ofDMF, and 2.58 g of benzophenone dimethyl acetal and 656 mg of CSA wereadded thereto, followed by stirring at 40° C. under reduced pressure for22.5 hours. DMF in the reaction mixture was distilled off under reducedpressure, 10 mL of ethyl acetate and 10 mL of water were added to theresidue, and the layers were separated. After the organic layer wasextracted, the aqueous layer was further extracted twice with 10 mL ofethyl acetate. The combined organic layers were washed with 10 mL ofsaturated brine, dried over magnesium sulfate, and filtered, followed bydistilling-off of ethyl acetate under reduced pressure. The resultingresidue was purified with silica gel chromatography (n-hexane:ethylacetate=1:1) to obtain 647 mg of acetal compound (3d) (yield: 25%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.94 (m, 1H), 3.81 (dd, J=7.0, 5.2 Hz, 2H), 3.91 (dd, J=11.8, 5.5 Hz,2H), 4.14 (dd, J=11.8, 3.8 Hz, 2H), 7.25 (m, 2H), 7.34 (m, 4H), 7.51 (m,4H)

Step (B) Synthesis Example B1 (Step B: R²=Methyl) Synthesis of2,2-dimethyl-5-methanesulfonyloxymethyl-1,3-dioxane (4a)

2,2-Dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) (5.00 g) was dissolvedin 67 mL of CH₂Cl₂, and 5.42 mL of triethylamine was added thereto,followed by cooling to −20° C. Further, 2.56 mL of mesyl chloride (MsCl)was added, and the resulting mixture was stirred at −20° C. for 1 hour.Thereafter, 50 mL of water was added to the reaction mixture to stop thereaction, and extraction was performed twice with 40 mL of CH₂Cl₂. Afterthe separated organic layers were washed with water, CH₂Cl₂ wasdistilled off under reduced pressure, and the resulting residue waspurified with silica gel chromatography (n-hexane:ethyl acetate=1:1) toobtain 6.22 g of compound (4a) (yield: 92%).

¹H-NMR (500 MHz, CDCl₃):

δ: 1.39 (s, 3H), 1.46 (s, 3H), 2.00 (m, 1H), 3.04 (s, 3H), 3.78 (dd, 2H,J=12, 3 Hz), 4.08 (dd, 2H, J=11.5, 2.5 Hz), 4.42 (d, 2H, J=7 Hz)

Synthesis Example B2 (Step B: R²=n-Propyl) Synthesis of2,2-di-n-propyl-5-methanesulfonyloxymethyl-1,3-dioxane (4b)

The compound (3b) obtained in Synthesis Example A1 (1.0 g) was dissolvedin 20 mL of CH₂Cl₂, and 1.03 mL of triethylamine was further addedthereto, followed by cooling to −20° C. Thereafter, 0.459 mL of MsCl wasadded to the reaction solution and stirred at −20° C. for 1 hour. Then,20 mL of water was added to the resulting reaction mixture to stop thereaction, and extraction was performed twice with 20 mL of CH₂Cl₂,followed by washing with 20 mL of saturated brine. After the resultingproduct was dried over magnesium sulfate and filtered, CH₂Cl₂ wasdistilled off under reduced pressure, and the resulting residue waspurified with silica gel chromatography (n-hexane:ethyl acetate=3:1) toobtain 1.27 g of compound (4b) (yield: 92%).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.93 (m, 6H), 1.36 (m, 4H), 1.58 (m, 1H), 1.76 (m, 2H), 1.95 (m, 1H),3.04 (s, 3H), 3.74 (dd, J=12.4, 3.3 Hz, 2H), 4.08 (dd, J=15.6, 3.3 Hz,2H), 4.43 (d, J=7.5 Hz, 2H)

Synthesis Example B3 (Step B: R²=n-Butyl) Synthesis of2,2-di-n-butyl-5-methanesulfonyloxymethyl-1,3-dioxane (4c)

The compound (3c) obtained in Synthesis Example A2 (156 mg) wasdissolved in 2.7 mL of CH₂Cl₂, and 0.14 mL of triethylamine was furtheradded thereto, followed by cooling to −20° C. Thereafter, 0.062 mL ofMsCl was added thereto, and the mixture was stirred at −20° C. for 1hour. Then, 1.8 mL of water was added to the resulting reaction mixtureto stop the reaction, extraction was performed twice with 1.8 mL ofCH₂Cl₂, and the organic layers were washed with 1.8 mL of saturatedbrine. After the resulting product was dried over magnesium sulfate andfiltered, CH₂Cl₂ was distilled off under reduced pressure, and theresulting residue was purified with silica gel chromatography(n-hexane:ethyl acetate=3:1) to obtain 169 mg of compound (4c) (yield:81%).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.92 (m, 6H), 1.30 (m, 8H), 1.61 (m, 2H), 1.78 (m, 2H), 1.96 (m, 1H),3.04 (s, 3H), 3.74 (dd, J=12.6, 3.6 Hz, 2H), 4.08 (dd, J=12.5, 3.5 Hz,2H), 4.43 (d, J=7.4 Hz, 2H)

Synthesis Example B4 (Step B: R²=Phenyl) Synthesis of2,2-diphenyl-5-methanesulfonyloxymethyl-1,3-dioxane (4d)

The compound (3d) obtained in Synthesis Example A3 (640 mg) wasdissolved in 9.6 mL of CH₂Cl₂, and 493 μL of triethylamine was furtheradded thereto, followed by cooling to −20° C. Thereafter, 220 μL of MsClwas added and stirred at −20° C. for 1 hour. Then, 6.4 mL of water wasadded to the resulting reaction mixture to stop the reaction, extractionwas performed twice with 6.4 mL of CH₂Cl₂, and the organic layers werewashed with 6.4 mL of saturated brine. After the resulting product wasdried over magnesium sulfate and filtered, CH₂Cl₂ was distilled offunder reduced pressure, and the resulting residue was purified withsilica gel chromatography (n-hexane:ethyl acetate=3:1) to obtain 729 mgof compound (4d) (yield: 88%).

¹H-NMR (500 MHz, CDCl₃)

δ: 2.06 (m, 1H), 3.03 (s, 3H), 3.95 (dd, J=12.2, 3.7 Hz, 2H), 4.18 (dd,J=12.2, 3.4 Hz, 2H), 4.51 (d, J=7.5 Hz, 2H), 7.25 (m, 1H), 7.30 (m, 3H),7.39 (m, 2H), 7.49 (m, 4H)

Step (C) Synthesis Example C1-1 (Step C: R²=Methyl, Base=TEA, andSolvent=Methyl Ethyl Ketone) Synthesis of2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (400.0 mg) wasdissolved in 6 mL of methyl ethyl ketone, and 12 μL of triethylamine and401.1 mg of sodium iodide were added thereto, followed by heating underreflux for 1.5 hours. Thereafter, methyl ethyl ketone in the reactionmixture was distilled off under reduced pressure. Then, 10 mL of CH₂Cl₂and 10 mL of water were added thereto, and the layers were separated.The water layer was extracted twice with 10 mL of CH₂Cl₂, and theorganic layers were washed by adding 5 mL of 5% sodium thiosulfate and 5mL of 1% sodium hydrogen carbonate water. The organic layers werefurther washed with 10 mL of water, and CH₂Cl₂ was distilled off underreduced pressure. The resulting residue was purified with silica gelchromatography (n-hexane:ethyl acetate=5:1) to obtain 394.1 g ofcompound (5a) (yield: 86%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.41 (s, 3H), 1.43 (s, 3H), 1.95 (m, 1H), 3.23 (d, J=7 Hz, 2H), 3.73(dd, J=12, 6.5 Hz, 2H), 4.01 (dd, J=11.5, 4 Hz, 2H)

Synthesis Example C1-2 (Step C: R²=n-Propyl) Synthesis of2,2-di-n-propyl-5-iodomethyl-1,3-dioxane (5b)

The compound (4b) obtained in Synthesis Example B2 (1.20 g) wasdissolved in 14.3 mL of methyl ethyl ketone, and 30 μL of triethylamineand 966 mg of sodium iodide were further added thereto, followed byheating under reflux for 2 hours. Methyl ethyl ketone in the reactionsolution was distilled off under reduced pressure, 15 mL of CH₂Cl₂ and15 mL of water were added, and the layers were separated. The waterlayer was extracted twice with 15 mL of CH₂Cl₂, and the organic layerswere washed with 7.5 mL of 5% sodium thiosulfate and 7.5 mL of 1% sodiumhydrogen carbonate water. The organic layers were further washed with 15mL of saturated brine. After the resulting product was dried overmagnesium sulfate and filtered, CH₂Cl₂ was distilled off under reducedpressure, and the resulting residue was purified with silica gelchromatography (n-hexane:ethyl acetate=10:1) to obtain 1.16 g ofcompound (5b) (yield: 86%).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.93 (t, J=7.3 Hz, 6H), 1.35 (m, 4H), 1.66 (m, 4H), 1.90 (m, 1H),3.25 (d, J=7.2 Hz, 2H), 3.71 (dd, J=11.8, 6.0 Hz, 2H), 4.01 (dd, J=11.9,3.9 Hz, 2H)

Synthesis Example C1-3 (Step C: R²=n-Butyl) Synthesis of2,2-di-n-butyl-5-iodomethyl-1,3-dioxane (5c)

The compound (4c) obtained in Synthesis Example B3 (169 mg) wasdissolved in 2.9 mL of methyl ethyl ketone, and 3.8 μL of triethylamineand 123 mg of sodium iodide were further added thereto, followed byheating under reflux for 2 hours. Subsequently, methyl ethyl ketone inthe reaction solution was distilled off under reduced pressure, 3 mL ofCH₂Cl₂ and 3 mL of water were added thereto, and the layers wereseparated. Then, the water layer was extracted twice with 3 mL ofCH₂Cl₂, and the organic layers were washed with 1.5 mL of 5% sodiumthiosulfate and 1.5 mL of 1% sodium hydrogen carbonate water. Theorganic layers were further washed with 3 mL of saturated brine. Afterthe resulting product was dried over magnesium sulfate and filtered,CH₂Cl₂ was distilled off under reduced pressure. The resulting residuewas purified with silica gel chromatography (n-hexane:ethylacetate=10:1) to obtain 139 mg of compound (5c) (yield: 75%).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.92 (m, 6H), 1.30 (m, 8H), 1.68 (m, 4H), 1.91 (m, 1H), 3.25 (d,J=7.2 Hz, 2H), 3.71 (dd, J=12.0, 6.2 Hz, 2H), 4.00 (dd, J=11.9, 4.0 Hz,2H)

Synthesis Example C1-4 (Step C: R²=Phenyl) Synthesis of2,2-diphenyl-5-iodomethyl-1,3-dioxane (5d)

The compound (4d) obtained in Synthesis Example B4 (729 mg) wasdissolved in 10.9 mL of methyl ethyl ketone, and 14.5 μL oftriethylamine and 470 mg of sodium iodide were further added thereto,followed by heating under reflux for 2 hours. Methyl ethyl ketone in thereaction solution was distilled off under reduced pressure, and 5 mL ofCH₂Cl₂ and 5 mL of water were added thereto, and the layers wereseparated. The water layer was extracted twice with 3 mL of CH₂Cl₂, andthe organic layers were washed with 2.5 mL of 5% sodium thiosulfate and2.5 mL of 1% sodium hydrogen carbonate water. The organic layers werefurther washed with 5 mL of saturated brine. After the resulting productwas dried over magnesium sulfate and filtered, CH₂Cl₂ was distilled offunder reduced pressure. The resulting residue was purified with silicagel chromatography (n-hexane:ethyl acetate=10:1) to obtain 726 mg ofcompound (5d) (yield: 91%).

¹H-NMR (500 MHz, CDCl₃)

δ: 2.10 (m, 1H), 3.25 (d, J=7.5 Hz, 2H), 3.84 (dd, J=11.7, 6.3 Hz, 2H),4.16 (dd, J=11.7, 3.8 Hz, 2H), 7.26 (m, 2H), 7.34 (m, 4H), 7.50 (m, 4H)

Synthesis Example C2-1 (Step C: Solvent=Acetone+Methyl Isobutyl Ketone)Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 3 mL of acetone and 3 mL of methyl isobutyl ketone in anargon atmosphere, and 9.3 μL of triethylamine and 301 mg of sodiumiodide were further added thereto, followed by heating under reflux for2 hours. Acetone and methyl isobutyl ketone in the reaction solutionwere distilled off under reduced pressure, 6 mL of CH₂Cl₂ and 6 mL ofwater were added thereto, and the layers were separated. The water layerwas extracted twice with 6 mL of CH₂Cl₂, the organic layers were washedwith 3 mL of 5% sodium thiosulfate and 3 mL of 1% sodium hydrogencarbonate water. After the organic layers were further washed with 6 mLof saturated brine and dried over magnesium sulfate, CH₂Cl₂ wasdistilled off under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain266 mg of compound (5a) (yield: 78%).

Synthesis Example C2-2 (Step C: Solvent=Acetone) Synthesis of2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 6 mL of acetone in an argon atmosphere. Then, 9.3 μL oftriethylamine and 301 mg of sodium iodide were further added thereto,and the mixture was heated under reflux for 2 hours. Acetone in thereaction solution was distilled off under reduced pressure, 6 mL ofCH₂Cl₂ and 6 mL of water were added thereto, and the layers wereseparated. The water layer was extracted twice with 6 mL of CH₂Cl₂, andthe organic layers were washed with 3 mL of 5% sodium thiosulfate and 3mL of 1% sodium hydrogen carbonate water. After the organic layers werefurther washed with 6 mL of saturated brine and dried over magnesiumsulfate, CH₂Cl₂ was distilled off under reduced pressure. The resultingresidue was purified with silica gel chromatography (n-hexane:ethylacetate=10:1) to obtain 204 mg of compound (5a) (yield: 59%).

Synthesis Example C2-3 (Step C: Solvent=Methyl Isobutyl Ketone)Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 6 mL of methyl isobutyl ketone in an argon atmosphere, and9.3 μL of triethylamine and 301 mg of sodium iodide were added thereto,followed by heating under reflux for 2 hours. Methyl isobutyl ketone inthe reaction solution was distilled off under reduced pressure, 6 mL ofCH₂Cl₂ and 6 mL of water were added thereto, and the layers wereseparated. The water layer was extracted twice with 6 mL of CH₂Cl₂, andthe organic layers were washed with 3 mL of 5% sodium thiosulfate and 3mL of 1% sodium hydrogen carbonate water. After the organic layers werefurther washed with 6 mL of saturated brine and dried over magnesiumsulfate, CH₂Cl₂ was distilled off under reduced pressure. The resultingresidue was purified with silica gel chromatography (n-hexane:ethylacetate=10:1) to obtain 190 mg of compound (5a) (yield: 55%).

Synthesis Example C3-1 (Step C: Alkali Metal Halide=Sodium Bromide)Synthesis of 2,2-dimethyl-5-bromomethyl-1,3-dioxane (5a-1)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 6 mL of methyl ethyl ketone in an argon atmosphere, and 9.3μL of triethylamine and 207 mg of sodium bromide were further addedthereto, followed by heating under reflux for 23 hours. Methyl ethylketone in the reaction solution was distilled off under reducedpressure, 6 mL of CH₂Cl₂ and 6 mL of water were added thereto, and thelayers were separated. The water layer was extracted twice with 6 mL ofCH₂Cl₂, and the organic layers were washed with 3 mL of 5% sodiumthiosulfate and 3 mL of 1% sodium hydrogen carbonate water. After theorganic layers were further washed with 6 mL of saturated brine anddried over magnesium sulfate, CH₂Cl₂ was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (n-hexane:ethyl acetate=10:1) to obtain 127 mg ofcompound (5a-1) (yield: 45%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.41 (s, 3H), 1.44 (s, 3H), 2.02 (m, 1H), 3.51 (d, J=7.1 Hz, 2H),3.80 (dd, J=12, 5.7 Hz, 2H), 4.05 (dd, J=12, 4 Hz, 2H)

Synthesis Example C4-1 (Step C: Base=Diisopropylethyleneamine) Synthesisof 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 6 mL of methyl ethyl ketone in an argon atmosphere, and 12μL of diisopropylethyleneamine and 301 mg of sodium iodide were furtheradded thereto, followed by heating under reflux for 2 hours. Methylethyl ketone in the reaction solution was distilled off under reducedpressure, 6 mL of CH₂Cl₂ and 6 mL of water were added thereto, and thelayers were separated. The water layer was extracted twice with 6 mL ofCH₂Cl₂, and the organic layers were washed with 3 mL of 5% sodiumthiosulfate and 3 mL of 1% sodium hydrogen carbonate water. After theorganic layers were further washed with 6 mL of saturated brine anddried over magnesium sulfate, CH₂Cl₂ was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (n-hexane:ethyl acetate=10:1) to obtain 262 mg ofcompound (5a) (yield: 78%).

Synthesis Example C4-2 (Step C: Base=Sodium Hydrogen Carbonate,Solvent=Methyl Ethyl Ketone) Synthesis of2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 6 mL of methyl ethyl ketone in an argon atmosphere, and 5.6mg of sodium hydrogen carbonate and 301 mg of sodium iodide were furtheradded thereto, followed by heating under reflux for 2 hours. Methylethyl ketone in the reaction solution was distilled off under reducedpressure, 6 mL of CH₂Cl₂ and 6 mL of water were added thereto, and thelayers were separated. The water layer was extracted twice with 6 mL ofCH₂Cl₂, and the organic layers were washed with 3 mL of 5% sodiumthiosulfate and 3 mL of 1% sodium hydrogen carbonate water. After theorganic layers were further washed with 6 mL of saturated brine anddried over magnesium sulfate, CH₂Cl₂ was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (n-hexane:ethyl acetate=10:1) to obtain 234 mg ofcompound (5a) (yield: 68%).

Synthesis Example C4-3 (Step C: Base=NaHCO₃, Solvent=Acetone) Synthesisof 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (15.0 g) wasdissolved in 225 mL of acetone, and 5.62 g of sodium hydrogen carbonateand 20.05 g of sodium iodide were added thereto, followed by heatingunder reflux for 19 hours. After a white solid was filtered and washedwith acetone, acetone was distilled off under reduced pressure, and 150mL of CH₂Cl₂ was added thereto. The organic layer was washed by adding50 mL of 5% sodium thiosulfate and 50 mL of 1% sodium hydrogen carbonatewater, and the layers were separated. Extraction was performed with 50mL of CH₂Cl₂, the organic layer was washed with 5% brine, and CH₂C1 wasdistilled off under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain14.00 g of compound (5a) (yield: 82%).

Synthesis Example C4-4 (Step C: Base=Potassium Hydrogen Carbonate)Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 6 mL of methyl ethyl ketone in an argon atmosphere, and 6.7mg of potassium hydrogen carbonate and 301 mg of sodium iodide werefurther added thereto, followed by heating under reflux for 2 hours.Methyl ethyl ketone in the reaction solution was distilled off underreduced pressure, 6 mL of CH₂Cl₂ and 6 mL of water were added thereto,and the layers were separated. The water layer was extracted twice with6 mL of CH₂Cl₂, and the organic layers were washed with 3 mL of 5%sodium thiosulfate and 3 mL of 1% sodium hydrogen carbonate water. Afterthe organic layers were further washed with 6 mL of saturated brine anddried over magnesium sulfate, CH₂Cl₂ was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (n-hexane:ethyl acetate=10:1) to obtain 106 mg ofcompound (5a) (yield: 31%).

Synthesis Example C4-5 (Step C: Base=Potassium Carbonate) Synthesis of2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 6 mL of methyl ethyl ketone in an argon atmosphere, andpotassium carbonate and 301 mg of sodium iodide were further addedthereto, followed by heating under reflux for 2 hours. Methyl ethylketone in the reaction solution was distilled off under reducedpressure, 6 mL of CH₂Cl₂ and 6 mL of water were added thereto, and thelayers were separated. The water layer was extracted twice with 6 mL ofCH₂Cl₂, and the organic layers were washed with 3 mL of 5% sodiumthiosulfate and 3 mL of 1% sodium hydrogen carbonate water. After theorganic layers were further washed with 6 mL of saturated brine anddried over magnesium sulfate, CH₂Cl₂ was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (n-hexane:ethyl acetate=10:1) to obtain 209 mg ofcompound (5a) (yield: 61%).

Synthesis Example C4-6 (Step C: Base=Sodium Carbonate) Synthesis of2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

The compound (4a) obtained in Synthesis Example B1 (300 mg) wasdissolved in 6 mL of methyl ethyl ketone in an argon atmosphere, andsodium carbonate and 301 mg of sodium iodide were further added thereto,followed by heating under reflux for 2 hours. Methyl ethyl ketone in thereaction solution was distilled off under reduced pressure, 6 mL ofCH₂Cl₂ and 6 mL of water were added thereto, and the layers wereseparated. The water layer was extracted twice with 6 mL of CH₂Cl₂, andthe organic layers were washed with 3 mL of 5% sodium thiosulfate and 3mL of 1% sodium hydrogen carbonate water. After the organic layers werefurther washed with 6 mL of saturated brine and dried over magnesiumsulfate, CH₂Cl₂ was distilled off under reduced pressure. The resultingresidue was purified with silica gel chromatography (n-hexane:ethylacetate=10:1) to obtain 270 mg of compound (5a) (yield: 79%).

Step (B′) Synthesis Example B1 (Step B′: Solvent=Dichloromethane)Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

2,2-Dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) (1.00 g) was dissolvedin 22.8 mL of dichloromethane (MDC), and 700.0 mg of imidazole and 2.08g of iodine were added thereto, followed by cooling to 0° C.Subsequently, 2.15 g of triphenylphosphine was added, and the mixturewas stirred at 25° C. for 2 hours. The reaction was then quenched with20 mL of water, and the resulting product was extracted twice with 10 mLof dichloromethane and washed with 20 mL of water. Dichloromethane wasdistilled off from the organic phases under reduced pressure, and theresulting residue was purified with silica gel chromatography(n-hexane:ethyl acetate=5:1) to obtain 1.38 g of2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a) (yield: 79%).

Synthesis Example B2 (Step B′: Solvent=THF) Synthesis of2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

2,2-Dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) (500.0 mg) was dissolvedin 3.4 mL of tetrahydrofuran, and cooled to 0° C. Thereafter, 1.08 g oftriphenylphosphine, 279.5 mg of imidazole, and 1.04 g of iodine wereadded thereto, and the mixture was stirred at 25° C. for 2.5 hours. Theresulting product was then washed with 10 mL of 5% aqueous sodiumthiosulfate solution, extracted with 20 mL of ethyl acetate, and washedwith 5% brine. After the organic phase was dried over magnesium sulfateand filtered, ethyl acetate was distilled off under reduced pressure.The resulting residue was purified with silica gel chromatography(n-hexane:ethyl acetate=5:1) to obtain 639.0 mg of2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a) (yield: 73%).

Synthesis Example B3 (Step B′: Solvent=CPME) Synthesis of2,2-dimethyl-5-bromomethyl-1,3-dioxane (5a)

2,2-Dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) (500.0 mg) was dissolvedin 6.8 mL of tetrahydrofuran, followed by cooling to 0° C. Thereafter,1.08 g of triphenylphosphine, 279.5 mg of imidazole, and 1.04 g ofiodine were added thereto, and the mixture was stirred at 25° C. for 2hours. After triphenylphosphine oxide was removed, and the resultingproduct was washed with 10 mL of CPME, the organic phase was washed with10 mL of 5% aqueous sodium thiosulfate solution, extracted 3 times with10 mL of CPME, and washed with 5% brine. CPME was distilled off underreduced pressure, and the resulting residue was purified with silica gelchromatography (n-hexane:ethyl acetate=5:1) to obtain 621.1 mg of2,2-dimethyl-5-bromomethyl-1,3-dioxane (5a) (yield: 71%).

Synthesis Example B4 (Step B′: Solvent=Dichloromethane) Synthesis of2,2-dimethyl-5-bromomethyl-1,3-dioxane (5b)

2,2-Dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) (1.00 g) was dissolvedin 22.8 mL of dichloromethane (MDC), and 700.0 mg of imidazole and 2.72g of carbon tetrabromide were added thereto. After ice-cooling, 2.15 gof triphenylphosphine was further added, and the mixture was stirred atroom temperature for 4 hours. Dichloromethane was distilled off underreduced pressure, and the resulting product was purified with silica gelchromatography (n-hexane:ethyl acetate=5:1) to quantitatively obtain1.60 g of 2,2-dimethyl-5-bromomethyl-1,3-dioxane (5b).

Step (D) Synthesis Example D1-1 (Step D: R²=Methyl) Synthesis of(2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Dimethyl Ester(6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (300.0 mg)was dissolved in 2.34 mL of DMF. Then, 763.4 mg of cesium carbonate and215 μL of dimethyl phosphite were further added thereto, followed bystirring at 40° C. for 5 hours. DMF in the reaction solution wasdistilled off under reduced pressure, and 5 mL of toluene was added tothe obtained residue. A white solid was then filtered. After the whitesolid was further washed with 5 mL of toluene, the obtained filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 255.6 mgof phosphonic acid dimethyl compound (6a) (yield: 92%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.42 (s, 6H), 1.82 (dd, J=18.5, 6.5 Hz, 2H), 2.15 (m, 1H), 3.66 (dd,J=11.5, 7 Hz, 2H), 3.75 (d, J=10.5 Hz, 6H), 4.01 (d, J=12, 3.5 Hz, 2H)

Synthesis Example D1-2 (Step D: R²=n-Propyl) Synthesis of(2,2-di-n-propyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Dimethyl Ester(6b)

The iodine compound (5b) obtained in Synthesis Example C1-2 (1.06 g) wasdissolved in 6.8 mL of DMF. Then, 2.21 g of cesium carbonate and 621 μLof dimethyl phosphite were further added thereto, followed by stirringat 40° C. for 3 hours. DMF in the reaction solution was distilled offunder reduced pressure, and 5 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 2.5 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=20:1) to obtain 767 mg ofphosphonic acid dimethyl compound (6b) (yield: 79%).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.91 (t, J=7.4 Hz, 6H), 1.36 (m, 4H), 1.66 (m, 4H), 1.84 (dd, J=18.7,6.9 Hz, 2H), 2.09 (m, 1H), 3.63 (dd, J=11.7, 6.6 Hz, 2H), 3.75 (d,J=10.9 Hz, 6H), 3.99 (dd, J=11.7, 3.8 Hz, 2H)

Synthesis Example D1-3 (Step D: R²=Butyl) Synthesis of(2,2-dibutyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Dimethyl Ester(6c)

The iodine compound (5c) obtained in Synthesis Example C1-3 (139 mg) wasdissolved in 1.2 mL of DMF. Then, 266 mg of cesium carbonate and 75 μLof dimethyl phosphite were further added thereto, followed by stirringat 50° C. for 3 hours. DMF in the reaction solution was distilled offunder reduced pressure, and 1 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 1 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 80.5 mgof phosphonic acid dimethyl compound (6c) (yield: 61%).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.91 (m, 6H), 1.30 (m, 8H), 1.68 (m, 4H), 1.83 (dd, J=18.7, 6.9 Hz,2H), 2.10 (m, 1H), 3.63 (dd. J=11.8, 6.7 Hz, 2H), 3.75 (d, J=10.9 Hz,6H), 3.99 (dd, J=11.7, 3.9 Hz, 2H)

Synthesis Example D1-4 (Step D: R²=Phenyl) Synthesis of(2,2-diphenyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Dimethyl Ester(6d)

The iodine compound (5d) obtained in Synthesis Example C1-4 (726 mg) wasdissolved in 5.7 mL of DMF. Then, 1.24 g of cesium carbonate and 350 μLof dimethyl phosphite were further added, followed by stirring at 50° C.for 3 hours. DMF in the reaction solution was distilled off underreduced pressure, and 4.2 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 2.1 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 621 mg ofphosphonic acid dimethyl compound (6d) (yield: 90%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.80 (dd, J=18.8, 7.0 Hz, 2H), 2.30 (m, 1H), 3.74 (d, J=10.9 Hz, 6H),3.77 (dd, J=11.5, 7.2 Hz, 2H), 4.15 (dd, J=11.5, 3.8 Hz, 2H), 7.26 (m,2H), 7.33 (m, 4H), 7.50 (m, 4H)

Synthesis Example D2-1 (Step D: R²=Methyl, Solvent=DMF) Synthesis of(2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Dimethyl Ester(6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 3.9 mL of DMF. Then, 1.27 g of cesium carbonate and 360μL of dimethyl phosphite were further added, followed by stirring at 50°C. for 3 hours. DMF in the reaction solution was distilled off underreduced pressure, and 10 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 10 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 406.0 mgof phosphonic acid dimethyl compound (6a) (yield: 87%).

Synthesis Example D2-2 (Step D: R²=Methyl, Solvent=DMAc) Synthesis of(2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Dimethyl Ester(6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 3.9 mL of DMAc. Then, 1.27 g of cesium carbonate and360 μL of dimethyl phosphite were further added, followed by stirring at50° C. for 3 hours. DMAc in the reaction solution was distilled offunder reduced pressure, and 10 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 10 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 438.7 mgof phosphonic acid dimethyl compound (6a) (yield: 94%).

Synthesis Example D2-3 (Step D: R²=Methyl, Solvent=Acetonitrile)Synthesis of (2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic AcidDimethyl Ester (6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 3.9 mL of acetonitrile. Then, 1.27 g of cesiumcarbonate and 360 μL of dimethyl phosphite were further added, followedby stirring at 50° C. for 24 hours. Acetonitrile in the reactionsolution was distilled off under reduced pressure, and 20 mL of toluenewas added to the obtained residue. A white solid was then filtered.After the white solid was further washed with 10 mL of toluene, theresulting filtrate was concentrated under reduced pressure, and theresidue was purified with silica gel chromatography(chloroform:methanol=10:1) to obtain 408.8 mg of phosphonic aciddimethyl compound (6a) (yield: 88%).

Synthesis Example D2-4 (Step D: R²=Methyl, Solvent=DMF/AN (1/1))Synthesis of (2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic AcidDimethyl Ester (6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 2.0 mL of DMF and 2.0 mL of acetonitrile. Then, 1.27 gof cesium carbonate and 360 μL of dimethyl phosphite were further added,followed by stirring at 50° C. for 18 hours. The solvent in the reactionsolution was distilled off under reduced pressure, and 20 mL of toluenewas added to the obtained residue. A white solid was then filtered.After the white solid was further washed with 10 mL of toluene, theresulting filtrate was concentrated under reduced pressure, and theresidue was purified with silica gel chromatography(chloroform:methanol=10:1) to obtain 404.1 mg of phosphonic aciddimethyl compound (6a) (yield: 87%).

Synthesis Example D3-1 (Step D: R²=Methyl, Base=Cesium Carbonate)Synthesis of (2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic AcidDimethyl Ester (6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 3.9 mL of DMF. Then, 1.27 g of cesium carbonate and 360μL of dimethyl phosphite were further added, followed by stirring at 50°C. for 3 hours. DMF in the reaction solution was distilled off underreduced pressure, and 10 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 10 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 406.0 mgof phosphonic acid dimethyl compound (6a) (yield: 87%).

Synthesis Example D3-2 (Step D: R²=Methyl, Base=Potassium Carbonate)Synthesis of (2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic AcidDimethyl Ester (6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 3.9 mL of DMF. Then, 540 mg of potassium carbonate and360 μL of dimethyl phosphite were further added, followed by stirring at50° C. for 24 hours. DMF in the reaction solution was distilled offunder reduced pressure, and 10 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 10 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 139.6 mgof phosphonic acid dimethyl compound (6a) (yield: 30%).

Synthesis Example D3-3 (Step D: R²=Methyl, Base=Rubidium Carbonate)Synthesis of (2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic AcidDimethyl Ester (6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 3.9 mL of DMF. Then, 902.1 mg of rubidium carbonate and360 μL of dimethyl phosphite were further added, followed by stirring at50° C. for 24 hours. DMF in the reaction solution was distilled offunder reduced pressure, and 10 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 10 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 280.7 mgof phosphonic acid dimethyl compound (6a) (yield: 60%).

Synthesis Example D3-4 (Step D: R²=Methyl, Base=Sodium Carbonate)Synthesis of (2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic AcidDimethyl Ester (6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 3.9 mL of DMF. Then, 414.0 mg of sodium carbonate and360 μL of dimethyl phosphite were further added, followed by stirring at50° C. for 24 hours. DMF in the reaction solution was distilled offunder reduced pressure, and 10 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 10 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, the residue was diluted withtoluene to a total volume of 5 mL, and the yield was quantitativelydetermined in the liquid. The yield was 1.2%.

Synthesis Example D3-5 (Step D: R²=Methyl, Base=Potassium HydrogenCarbonate) Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic Acid Dimethyl Ester (6a)

The iodine compound (5a) obtained in Synthesis Example C1-1 (500.0 mg)was dissolved in 3.9 mL of DMF. Then, 391.1 mg of potassium hydrogencarbonate and 360 μL of dimethyl phosphite were further added, followedby stirring at 50° C. for 24 hours. DMF in the reaction solution wasdistilled off under reduced pressure, and 10 mL of toluene was added tothe obtained residue. A white solid was then filtered. After the whitesolid was further washed with 10 mL of toluene, the resulting filtratewas concentrated under reduced pressure, the residue was toluene to atotal volume of 5 mL, and the yield was quantitatively determined in theliquid. The yield was 3.5%.

Synthesis Example D4-1 (Step D: X=Bromine) Synthesis of(2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Dimethyl Ester(6a)

The bromine compound (5a-1) obtained in Synthesis Example C3-1 (93.7 mg)was dissolved in 0.9 mL of DMF. Then, 292 mg of cesium carbonate and82.1 μL of dimethyl phosphite were further added, followed by stirringat 50° C. for 4 hours. DMF in the reaction solution was distilled offunder reduced pressure, and 5 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 10 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 89.3 mgof phosphonic acid dimethyl compound (6a) (yield: 84%).

Synthesis Example D5-1 (Step D: R¹=Ethyl) Synthesis of(2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Diethyl Ester(6a-1)

The iodine compound (5a) obtained in Synthesis Example C1-1 (2.00 g) wasdissolved in 15.6 mL of DMF. Then, 5.09 g of cesium carbonate and 2.01mL of diethyl phosphite were further added, followed by stirring at 50°C. for 3 hours. DMF in the reaction solution was distilled off underreduced pressure, and 20 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 30 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to quantitativelyobtain 2.24 g of phosphonic acid diethyl compound (6a-1).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.33 (t, J=7 Hz, 6H), 1.42 (s, 3H), 1.42 (s, 3H), 1.76 (dd, J=19, 7Hz, 2H), 2.18 (m, 1H), 3.66 (dd, J=11.5, 7.5 Hz, 2H), 4.00 (dd, J=11.5,4 Hz, 2H), 4.10 (m, 4H)

Synthesis Example D5-2 (Step D: R¹=n-Butyl) Synthesis of(2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Diethyl Ester(6a-2)

The iodine compound (5a) obtained in Synthesis Example C1-1 (2.00 g) wasdissolved in 15.6 mL of DMF. Then, 5.09 g of cesium carbonate and 3.05mL of dibutyl phosphite were further added, followed by stirring at 50°C. for 3 hours. DMF in the reaction solution was distilled off underreduced pressure, and 20 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 20 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to quantitativelyobtain 2.74 g of phosphonic acid dibutyl compound (6a-2).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.94 (t, J=7.5 Hz, 6H), 1.40 (tq, J=7.5, 7.5 Hz, 4H), 1.42 (s, 6H),1.65 (tt, J=8, 8 Hz, 4H), 1.75 (dd, J=19, 7 Hz, 2H), 2.17 (m, 1H), 3.66(dd, J=11.5, 7.5 Hz, 2H), 4.03 (m, 6H)

Synthesis Example D5-3 (Step D: R²=Ethyl) Synthesis of(2,2-dimethyl-[1,3]dioxan-5-yl methyl)-phosphonic Acid Diethyl Ester(6a-3)

The iodine compound (5a) obtained in Synthesis Example C1-1 (1.00 g) wasdissolved in 7.8 mL of DMF. Then, 2.54 g of cesium carbonate and 1.74 mLof dibenzyl phosphite were further added, followed by stirring at 50° C.for 3 hours. DMF in the reaction solution was distilled off underreduced pressure, and 10 mL of toluene was added to the obtainedresidue. A white solid was then filtered. After the white solid wasfurther washed with 20 mL of toluene, the resulting filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified with silica gel chromatography (n-hexane:ethyl acetate=1:2) toquantitatively obtain 1.58 g of phosphonic acid dibenzyl compound(6a-3).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.38 (s, 3H), 1.39 (s, 3H), 1.77 (dd, J=19, 7 Hz, 2H), 2.11 (m, 1H),3.58 (dd, J=11.5, 7 Hz, 2H), 3.93 (dd, 12, 4 Hz, 2H), 5.00 (m, 4H), 7.34(m, 10H)

Step (E) Synthesis Example E1-1 (Step E: R²=Methyl) Synthesis of(2,3-dihydroxypropyl)-phosphonic Acid Dimethyl Ester (7a)

The phosphonic acid dimethyl compound (6a) obtained in Synthesis ExampleD1-1 (5.00 g) was dissolved in 125 mL of methanol, and 798.5 mg ofp-toluenesulfonic acid monohydrate was further added thereto, followedby stirring at 20° C. for 3 hours. The reaction was stopped with 640 μLof triethylamine, and methanol in the reaction solution was distilledoff under reduced pressure. The resulting residue was purified withsilica gel chromatography (chloroform:methanol=10:1) to obtain 3.82 g ofdiol compound (7a) (yield: 92%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.93 (dd, J=18.5, 7 Hz, 2H), 2.13 (m, 1H), 2.87 (dd, J=6, 6 Hz, 2H),3.77 (m, 10H)

Synthesis Example E1-2 (Step E: R²=n-Propyl) Synthesis of2-(dimethylphosphono)methyl-1,3-propanediol (7a)

The phosphonic acid dimethyl compound (6b) obtained in Synthesis ExampleD1-2 (687 mg) was dissolved in 4.7 mL of methanol, and 22.0 mg ofp-toluenesulfonic acid monohydrate was further added thereto, followedby stirring at 20° C. for 3 hours. Then, methanol in the reactionsolution was distilled off under reduced pressure. The resulting residuewas purified with silica gel chromatography (chloroform:methanol=5:1) toobtain 361 mg of diol compound (7a) (yield: 78%).

Synthesis Example E1-3 (Step E: R²=Butyl) Synthesis of2-(dimethylphosphono)methyl-1,3-propanediol (7a)

The phosphonic acid dimethyl compound (6c) obtained in Synthesis ExampleD1-3 (80.5 mg) was dissolved in 0.75 mL of methanol, and 2.4 mg ofp-toluenesulfonic acid monohydrate was further added thereto, followedby stirring at 20° C. for 3 hours. Then, methanol in the reactionsolution was distilled off under reduced pressure. The resulting residuewas purified with silica gel chromatography (chloroform:methanol=10:1)to obtain 37.5 mg of diol compound (7a) (yield: 76%).

Synthesis Example E1-4 (Step E: R²=Phenyl) Synthesis of2-(dimethylphosphono)methyl-1,3-propanediol (7a)

The phosphonic acid dimethyl compound (6d) obtained in Synthesis ExampleD1-4 (621 mg) was dissolved in 5.1 mL of methanol, and 16.3 mg ofp-toluenesulfonic acid monohydrate was further added thereto, followedby stirring at 0° C. for 15 hours and at 20° C. for 1 hour. Then,methanol in the reaction solution was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (chloroform:methanol=10:1) to obtain 226 mg of diolcompound (7a) (yield: 67%).

Synthesis Example E2-1 (Step E: R²=Ethyl) Synthesis of2-(diethylphosphono)methyl-1,3-propanediol (7a-1)

The phosphonic acid diethyl compound (6a-1) obtained in SynthesisExample D5-1 (2.00 g) was dissolved in 15 mL of methanol, and 428.6 mgof p-toluenesulfonic acid monohydrate was further added thereto,followed by stirring at 20° C. for 3 hours, and then at 0° C. overnight.Methanol in the reaction solution was distilled off under reducedpressure, and the resulting residue was purified with silica gelchromatography (chloroform:methanol=5:1) to obtain 1.69 g of diolcompound (7a-1) (yield: 99%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.34 (t, J=7 Hz, 6H), 1.91 (dd, J=18.5, 7 Hz, 2H), 2.14 (m, 1H), 3.20(br, hydroxyl group), 3.77 (d, J=5 Hz, 4H), 4.12 (m, 4H)

Synthesis Example E2-2 (Step E: R²=n-Butyl) Synthesis of2-(dibutylphosphono)methyl-1,3-propanediol (7a-2)

The phosphonic acid dibutyl compound (6a-2) obtained in SynthesisExample D5-2 (2.50 g) was dissolved in 15.5 mL of methanol, and 442.5 mgof p-toluenesulfonic acid monohydrate was further added thereto,followed by stirring at 20° C. for 8 hours. Methanol in the reactionsolution was distilled off under reduced pressure. The resulting residuewas purified with silica gel chromatography (chloroform:methanol=15:1)to obtain 2.13 g of diol compound (7a-2) (yield: 97%).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.94 (t, J=7.5 Hz, 6H), 1.41 (tq, J=7.5, 7.5 Hz, 4H), 1.66 (tt, J=8,8 Hz, 4H), 1.90 (dd, J=19, 7 Hz, 2H), 2.12 (m, 1H), 3.76 (m, 4H), 4.04(m, 4H)

Synthesis Example E2-3 (Step E: R²=Benzyl) Synthesis of2-(dibenzylphosphono)methyl-1,3-propanediol (7a-3)

The phosphonic acid dibenzyl compound (6a-3) obtained in SynthesisExample D5-3 (1.58 g) was dissolved in 8.1 mL of methanol, and 230.9 mgof p-toluenesulfonic acid monohydrate was further added thereto,followed by stirring at 20° C. for 3 hours, and then at 0° C. overnight.Methanol in the reaction solution was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (chloroform:methanol=10:1) to obtain 1.2/g of diolcompound (7a-3) (yield: 89%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.92 (dd, J=19, 7 Hz, 2H), 2.05 (m, 1H), 3.70 (m, 4H), 5.01 (m, 4H),7.34 (m, 10H)

Step (F) Synthesis Example F1-1 (Step F: Base=DBU, Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (200.0 mg) wasdissolved in 4 mL of DMF, and 45.3 μL of DBU was further added thereto,followed by stirring at 20° C. for 3 hours. Then, 57.6 mg ofp-toluenesulfonic acid monohydrate was added to the reaction mixture tostop the reaction, and DMF in the reaction solution was distilled offunder reduced pressure. The resulting residue was purified with silicagel chromatography (chloroform:methanol=9:1) to obtain 147.1 mg ofcyclic phosphonic acid compound (8a) (yield: 88%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.73-2.07 (m, 3H), 2.35 (dd, J=5, 5 Hz, 1H), 2.68-2.88 (m, 1H),3.65-3.73 (m, 2H), 3.79 (dd, J=11, 3.5 Hz, 3H), 3.89-4.37 (m, 2H)

Synthesis Example F1-2 (Step F: Base=DBU, Solvent=DMAc) Synthesis of(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500 mg) wasdissolved in 10.2 mL of dimethylformacetamide, and 113 μL of DBU wasfurther added thereto, followed by stirring at 20° C. for 3 hours. Thereaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate,and dimethylformacetamide in the reaction solution was distilled offunder reduced pressure. The resulting residue was purified with silicagel chromatography (chloroform:methanol=5:1) to obtain 212 mg of cyclicphosphonic acid compound (8a) (yield: 51%).

Synthesis Example F1-3 (Step F: Base=DBU, Solvent=Acetonitrile (AN))Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500 mg) wasdissolved in 10.2 mL of acetonitrile, and 113 μL of DBU was furtheradded thereto, followed by stirring at 20° C. for 3 hours. The reactionwas stopped with 144 mg of p-toluenesulfonic acid monohydrate, andacetonitrile in the reaction solution was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (chloroform:methanol=10:1) to obtain 235 mg of cyclicphosphonic acid compound (8a) (yield: 56%).

Synthesis Example F1-4 (Step F: Base=DBU, Solvent=Acetone) Synthesis of(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500 mg) wasdissolved in 10.2 mL of acetone, and 113 μL of DBU was further addedthereto, followed by stirring at 20° C. for 3 hours. The reaction wasstopped with 144 mg of p-toluenesulfonic acid monohydrate, and acetonein the reaction solution was distilled off under reduced pressure. Theresulting residue was purified with silica gel chromatography(chloroform:methanol=10:1) to obtain 224 mg of cyclic phosphonic acidcompound (8a) (yield: 54%).

Synthesis Example F1-4 (Step F: Base=DBU, Solvent=Methanol) Synthesis of(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500 mg) wasdissolved in 10.2 mL of methanol, and 113 μL of DBU was further addedthereto, followed by stirring at 20° C. for 3 hours. The reaction wasstopped with 144 mg of p-toluenesulfonic acid monohydrate, and methanolin the reaction solution was distilled off under reduced pressure. Theresulting residue was purified with silica gel chromatography(chloroform:methanol=10:1) to obtain 86.8 mg of cyclic phosphonic acidcompound (8a) (yield: 21%).

Synthesis Example F1-5 (Step F: Base=DBU, Solvent=Isopropanol) Synthesisof (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500 mg) wasdissolved in 10.2 mL of isopropanol, and 113 μL of DBU was further addedthereto, followed by stirring at 20° C. for 3 hours. The reaction wasstopped with 144 mg of p-toluenesulfonic acid monohydrate, andisopropanol in the reaction solution was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (chloroform:methanol=10:1) to obtain 75 mg of cyclicphosphonic acid compound (8a) (yield: 18%).

Synthesis Example F1-6 (Step F: Base=DBU, Solvent=Butanol) Synthesis of(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500 mg) wasdissolved in 10.2 mL of butanol, and 113 μL of DBU was further addedthereto, followed by stirring at 20° C. for 3 hours. The reaction wasstopped with 144 mg of p-toluenesulfonic acid monohydrate, and butanolin the reaction solution was distilled off under reduced pressure. Theresulting residue was purified with silica gel chromatography(chloroform:methanol=10:1) to obtain 121 mg of cyclic phosphonic acidcompound (5a) (yield: 29%).

Synthesis Example F1-7 (Step F: Base=DBU, Solvent=DMF/acetonitrile)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl) methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500 mg) wasdissolved in 5.1 mL of DMF and 5.1 mL of acetonitrile. Then, 113 μL ofDBU was further added thereto, followed by stirring at 20° C. for 3hours. The reaction was stopped with 144 mg of p-toluenesulfonic acidmonohydrate, and DMF and acetonitrile in the reaction solution weredistilled off under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (chloroform:methanol=10:1) to obtain 170mg of cyclic phosphonic acid compound (5a) (yield: 41%).

Synthesis Example F2-1 (Step F: Base=DBU (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl) methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 113 μL of DBU was further added thereto,followed by stirring at 20° C. for 3 hours. The reaction was stoppedwith 144 mg of p-toluenesulfonic acid monohydrate, and DMF was distilledoff under reduced pressure. The resulting residue was purified withsilica gel chromatography (chloroform:methanol=15:1) to obtain 304.7 mgof cyclic phosphonic acid compound (8a) (yield: 73%).

Synthesis Example F2-2 (Step F: Base=DBN (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 90 μL of DBN was further added thereto,followed by stirring at 20° C. for 4 hours. The reaction was stoppedwith 144 mg of p-toluenesulfonic acid monohydrate, and DMF in thereaction solution was distilled off under reduced pressure. Theresulting residue was purified with silica gel chromatography(chloroform:methanol=15:1) to obtain 307.2 mg of cyclic phosphonic acidcompound (8a) (yield: 73%).

Synthesis Example F2-3 (Step F: Base=TEA (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 105 μL of TEA was further added thereto.Then, the resulting mixture was heated to increase the temperature from20° C. to a reflux temperature, followed by stirring for 2.5 hours. Thereaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate,and DMF in the reaction solution was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (chloroform:methanol=15:1) to obtain 216.2 mg of cyclicphosphonic acid compound (8a) (yield: 52%).

Synthesis Example F2-4 (Step F: Base=DIPEA (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 132 μL of DIPEA was further addedthereto. Then, the resulting mixture was heated to increase thetemperature from 20° C. to a reflux temperature, followed by stirringfor 2.5 hours. The reaction was stopped with 144 mg of p-toluenesulfonicacid monohydrate, and DMF in the reaction solution was distilled offunder reduced pressure. The resulting residue was purified with silicagel chromatography (chloroform:methanol=15:1) to obtain 226.1 mg ofcyclic phosphonic acid compound (8a) (yield: 54%).

Synthesis Example F2-5 (Step F: Base=NaOMe (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl) methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 40.9 mg of sodium methoxide was furtheradded thereto, followed by stirring at 20° C. for 3 hours. The reactionwas stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMFin the reaction solution was distilled off under reduced pressure. Then,10 mL of chloroform was added to the residue. A white salt was filtered,and the white solid was washed with 10 mL of chloroform, and thefiltrate was concentrated. The resulting residue was purified withsilica gel chromatography (chloroform:methanol=15:1) to obtain 258.1 mgof cyclic phosphonic acid compound (8a) (yield: 62%).

Synthesis Example F2-6 (Step F: Base=NaOEt (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (770.7 mg) wasdissolved in 15.4 mL of DMF, and 79.4 mg of sodium ethoxide was furtheradded thereto, followed by stirring at 20° C. for 3 hours. The reactionwas stopped with 221.9 mg of p-toluenesulfonic acid monohydrate, and DMFin the reaction solution was distilled off under reduced pressure. Then,20 mL of chloroform was added to the residue. A white salt was filtered,the white solid was washed with 20 mL of chloroform, and the filtratewas concentrated. The resulting residue was purified with silica gelchromatography (chloroform:methanol=15:1) to obtain 349.0 mg of cyclicphosphonic acid compound (8a) (yield: 54%).

Synthesis Example F2-7 (Step F: Base=t-BuOK (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 84.9 mg of potassium tert-butoxide wasfurther added thereto, followed by stirring at 20° C. for 3 hours. Thereaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate,and DMF in the reaction solution was distilled off under reducedpressure. Then, 10 mL of chloroform was added to the residue. A whitesalt was filtered, the white solid was washed with 10 mL of chloroform,and the filtrate was concentrated. The resulting residue was purifiedwith silica gel chromatography (chloroform:methanol=15:1) to obtain193.8 mg of cyclic phosphonic acid compound (8a) (yield: 46%).

Synthesis Example F2-8 (Step F: Base=t-BuONa (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 72.7 mg of sodium tert-butoxide wasfurther added thereto, followed by stirring at 20° C. for 3 hours. Thereaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate,and the precipitated white solid was filtered. After the white solid waswashed with 5 mL of DMF, DMF was distilled off from the filtrate underreduced pressure. Then, 10 mL of chloroform was added to the residue. Awhite salt was filtered. After washing with 10 mL of chloroform, thefiltrate was concentrated. The resulting residue was purified withsilica gel chromatography (chloroform:methanol=15:1) to obtain 200.6 mgof cyclic phosphonic acid compound (8a) (yield: 48%).

Synthesis Example F2-9 (Step F: Base=CsCO₃ (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 246.6 mg of cesium carbonate was furtheradded thereto, followed by stirring at 20° C. for 3 hours. The reactionwas stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMFin the reaction solution was distilled off under reduced pressure. Then,10 mL of chloroform was added to the residue. A white salt was filtered.After the white solid was washed with 10 mL of chloroform, the filtratewas concentrated. The resulting residue was purified with silica gelchromatography (chloroform:methanol=15:1) to obtain 35.1 mg of cyclicphosphonic acid compound (8a) (yield: 8%).

Synthesis Example F2-10 (Step F: Base=NaH (0.3 Eq.), Solvent=DMF)Synthesis of (2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 30.3 mg of sodium hydride was furtheradded thereto, followed by stirring at 20° C. for 3 hours. The reactionwas stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMFin the reaction solution was distilled off under reduced pressure. Then,10 mL of chloroform was added to the residue. A white salt was filtered.After the white solid was washed with 10 mL of chloroform, the filtratewas concentrated. The resulting residue was purified with silica gelchromatography (chloroform:methanol=15:1) to obtain 190.2 mg of cyclicphosphonic acid compound (8a) (yield: 45%).

Synthesis Example F3-1 (Step F: Quenching Agent=CSA) Synthesis of(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 113 μL of DBU was further added thereto,followed by stirring at 20° C. for 3 hours. The reaction was stoppedwith 175.9 mg of camphorsulfonic acid (CSA), and DMF in the reactionsolution was distilled off under reduced pressure. The resulting residuewas purified with silica gel chromatography (chloroform:methanol=15:1)to quantitatively obtain 554.2 mg of cyclic phosphonic acid compound(8a).

Synthesis Example F3-2 (Step F: Quenching Agent=Formic Acid)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 113 μL of DBU was further added thereto,followed by stirring at 20° C. for 3 hours. The reaction was stoppedwith 30 μL of formic acid, and DMF in the reaction solution wasdistilled off under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (chloroform:methanol=15:1) to obtain305.6 mg of cyclic phosphonic acid compound (8a) (yield: 73%).

Synthesis Example F3-3 (Step F: Quenching Agent=Acetic Acid)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 113 μL of DBU was further added thereto,followed by stirring at 20° C. for 3 hours. The reaction was stoppedwith 43 μL of acetic acid, and DMF in the reaction solution wasdistilled off under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (chloroform:methanol=15:1) to obtain289.6 mg of cyclic phosphonic acid compound (8a) (yield: 69%).

Synthesis Example F3-4 (Step F: Quenching Agent=Propionic Acid)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 113 μL of DBU was further added thereto,followed by stirring at 20° C. for 3 hours. The reaction was stoppedwith 57 μL of propionic acid, and DMF in the reaction solution wasdistilled off under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (chloroform:methanol=15:1) to obtain303.0 mg of cyclic phosphonic acid compound (8a) (yield: 72%).

Synthesis Example F3-5 (Step F: Quenching Agent=Butyric Acid)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 113 μL of DBU was further added thereto,followed by stirring at 20° C. for 3 hours. The reaction was stoppedwith 69 μL of butyric acid, and DMF in the reaction solution wasdistilled off under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (chloroform:methanol=15:1) to obtain303.3 mg of cyclic phosphonic acid compound (8a) (yield: 72%).

Synthesis Example F3-6 (Step F: Quenching Agent=Trifluoroacetic Acid)

The diol compound (7a) obtained in Synthesis Example E1-1 (500.0 mg) wasdissolved in 10 mL of DMF, and 113 UL of DBU was further added thereto,followed by stirring at 20° C. for 3 hours. The reaction was stoppedwith 58 μL of trifluoroacetic acid, and DMF in the reaction solution wasdistilled off under reduced pressure. The resulting residue was purifiedwith silica gel chromatography (chloroform:methanol=15:1) to obtain288.4 mg of cyclic phosphonic acid compound (8a) (yield: 69%).

Synthesis Example F4-1 (Step F: Base=DBU, Solvent=Acetonitrile (AN))Synthesis of (2-ethoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a-1)

The diol compound (7a-1) obtained in Synthesis Example E2-1 (1.50 g) wasdissolved in 26.5 mL of DMF, and 297 UL of DBU was further addedthereto, followed by stirring at 20° C. for 3 hours. Further, 200 μL ofDBU was added to this solution, and the resulting mixture was stirred at20° C. for 2 hours. Subsequently, the reaction was stopped with 630.7 mgof p-toluenesulfonic acid monohydrate, and DMF in the reaction solutionwas distilled off under reduced pressure. The resulting residue waspurified with silica gel chromatography (chloroform:methanol=15:1), theobtained fraction was dissolved again in 25.1 mL of DMF, and 282 μL ofDBU was added thereto, followed by stirring at 20° C. for 4 hours.Further, 282 μL of DBU was added to this solution, and the resultingmixture was stirred at 20° C. for 3 hours. Additionally, 282 μL of DBUwas added thereto, and the resulting mixture was stirred at 20° C. for 3hours. The reaction was then stopped with 1.08 g of p-toluenesulfonicacid monohydrate, and DMF in the reaction solution was distilled offunder reduced pressure. The resulting residue was purified with silicagel chromatography (chloroform:methanol=15:1) to obtain 781.6 mg ofcyclic phosphonic acid compound (8a-1) (yield: 69%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.35 (t, J=7 Hz, 3H), 1.75 (m, 1H), 1.85 (br, Hydroxyl group), 2.00(m, 1H), 2.15 (br, Hydroxyl group), 2.78 (m, 1H), 3.70 (m, 2H),3.89-4.36 (m, 4H)

Synthesis Example F4-2 (Step F: Base=DBU, Solvent=Acetonitrile (AN))Synthesis of (2-ethoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a-1)

The diol compound (7a-1) obtained in Synthesis Example E2-1 (1.50 g) wasdissolved in 26.5 mL of DMF, and 297 μL of DBU was further addedthereto, followed by stirring at 20° C. for 3 hours. Further, 200 μL ofDBU was added to this solution, and the resulting mixture was stirred at20° C. for 2 hours. Subsequently, the reaction was stopped with 630.7 mgof p-toluenesulfonic acid monohydrate, and DMF in the reaction solutionwas distilled off under reduced pressure. The resulting residue waspurified with silica gel chromatography (chloroform:methanol=15:1), theobtained fraction was dissolved again in 25.1 mL of DMF, and 282 μL ofDBU was added thereto, followed by stirring at 20° C. for 4 hours.Further, 282 μL of DBU was added to this solution, and the resultingmixture was stirred at 20° C. for 3 hours. Additionally, 282 μL of DBUwas added thereto, and the resulting mixture was stirred at 20° C. for 3hours. The reaction was then stopped with 1.08 g of p-toluenesulfonicacid monohydrate, and DMF in the reaction solution was distilled offunder reduced pressure. The resulting residue was purified with silicagel chromatography (chloroform:methanol=15:1) to obtain 781.6 mg ofcyclic phosphonic acid compound (8a-1) (yield: 69%).

Synthesis Example F4-3 (Step F: R²=n-Bu) Synthesis of(2-butoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a-2)

The diol compound (7a-2) obtained in Synthesis Example E2-2 (1.72 g) wasdissolved in 24.4 mL of DMF, and 911 μL of DBU was further addedthereto, followed by stirring at 60° C. for 5 hours. The reaction wasthen stopped with 1.16 g of p-toluenesulfonic acid monohydrate, and DMFin the reaction solution was distilled off under reduced pressure. Theresulting residue was purified with silica gel chromatography(chloroform:methanol=10:1) to obtain 1.03 g of cyclic phosphonic acidcompound (8a-2) (yield: 81%).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.94 (t, J=7.5 Hz, 6H), 1.40 (tq, J=7.5, 7.5 Hz, 4H), 1.64-1.79 (m,3H), 2.00 (m, 1H), 2.36 (br, Hydroxyl group), 2.69-2.89 (m, 1H), 3.70(m, 2H), 3.89-4.36 (m, 2H), 4.10 (m, 2H)

Synthesis Example F4-4 (Step F: R¹=Benzyl) Synthesis of(2-benzyloxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol (8a-3)

The diol compound (7a-3) obtained in Synthesis Example E2-3 (350.4 mg)was dissolved in 4 mL of DMF, and 45 μL of DBU was further addedthereto, followed by stirring at 20° C. for 3 hours. Subsequently, thereaction was stopped with 57.1 mg of p-toluenesulfonic acid monohydrate,and DMF in the reaction solution was distilled off under reducedpressure. The resulting residue was purified with silica gelchromatography (chloroform:methanol=5:1) to obtain 188.5 mg of cyclicphosphonic acid compound (8a-3) (yield: 78%).

¹H-NMR (500 MHz, CDCl₃)

δ: 1.65-2.06 (m, 2H), 2.66-2.80 (m, 1H), 3.61-3.67 (m, 2H), 3.88-4.36(m, 2H), 5.12 (m, 2H), 7.33-7.41 (m, 5H)

Step (G) Synthesis Example G1-1 (Step G: Solvent=Dichloromethane)Synthesis of 9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of dichloromethane. Then, 510.1mg of oleic acid and 66.2 mg of DMAP were further added thereto,followed by cooling to 0° C. Subsequently, 415.4 mg of EDC was added tothis solution, and the resulting mixture was stirred at room temperaturefor 2.5 hours. The reaction was stopped with 10 mL of 1N hydrochloricacid, and after the layers were separated, extraction was performed with10 mL of dichloromethane, and again with 5 mL of dichloromethane,followed by washing of the organic phases with 10 mL of 1% brine.Thereafter, dichloromethane was distilled off under reduced pressure,and purification was performed by silica gel chromatography (only ethylacetate) to obtain 649.8 mg of phosphonic acid ester compound (9a)(yield: 84%).

¹H-NMR (500 MHz, CDCl₃):

δ: 0.88 (t, J=6.5 Hz, 3H), 1.27-1.30 (m, 20H), 1.60-1.76 (m, 3H)2.01-2.12 (m, 5H), 2.32 (t, J=7.5 Hz, 2H), 2.83-2.97 (m, 1H), 3.78-4.34(m, 7H), 5.31-5.38 (m, 2H)

Synthesis Example G1-2 (Step G: Solvent=Toluene) Synthesis of9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of toluene. Then, 510.1 mg ofoleic acid and 66.2 mg of DMAP were further added thereto, followed bycooling to 0° C. Subsequently, 415.4 mg of EDC was added to thissolution, and the resulting mixture was stirred at room temperature for4 hours. The reaction was stopped with 10 mL of 1N hydrochloric acid,and 2 mL of methanol was added thereto. After the layers were separated,extraction was performed 3 times with 10 mL of toluene, followed bywashing of the organic phases with 10 mL of 1% brine. Thereafter,toluene was distilled off under reduced pressure, and purification wasperformed by silica gel chromatography (only ethyl acetate) to obtain369.1 mg of phosphonic acid ester compound (9a) (yield: 47%).

Synthesis Example G1-3 (Step G: Solvent=THF) Synthesis of 9-octadecenoicacid (9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of tetrahydrofuran. Then, 510.1mg of oleic acid and 66.2 mg of DMAP were further added thereto,followed by cooling to 0° C. Subsequently, 415.4 mg of EDC was added tothis solution, and the resulting mixture was stirred at room temperaturefor 4 hours. Then, tetrahydrofuran was distilled off under reducedpressure, and 10 mL of dichloromethane and 10 mL of 1N hydrochloric acidwere added thereto. After the resulting mixture was separated intolayers, extraction was performed twice with 10 mL of dichloromethane,followed by washing of the organic phases with 10 mL of 1% brine.Thereafter, dichloromethane was distilled off under reduced pressure,and purification was performed by silica gel chromatography (only ethylacetate) to obtain 509.6 mg of phosphonic acid ester compound (9a)(yield: 66%).

Synthesis Example G1-4 (Step G: Solvent=DMF) Synthesis of 9-octadecenoicacid (9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of N,N-dimethylformamide. Then,510.1 mg of oleic acid and 66.2 mg of DMAP were further added thereto,followed by cooling to 0° C. Subsequently, 415.4 mg of EDC was added tothis solution, and the resulting mixture was stirred at room temperaturefor 2.5 hours. Then, N,N-dimethylformamide was distilled off underreduced pressure, and 10 mL of dichloromethane and 10 mL of 1Nhydrochloric acid were added thereto. After the resulting mixture wasseparated into layers, extraction was performed twice with 10 mL ofdichloromethane, followed by washing of the organic phases with 10 mL of1% brine. Thereafter, dichloromethane was distilled off under reducedpressure, and purification was performed by silica gel chromatography(only ethyl acetate) to obtain 603.4 mg of phosphonic acid estercompound (9a) (yield: 78%).

Synthesis Example G1-5 (Step G: Solvent=Ethyl Acetate) Synthesis of9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of ethyl acetate. Then, 510.1 mgof oleic acid and 66.2 mg of DMAP were further added thereto, followedby cooling to 0° C. Subsequently, 415.4 mg of EDC was added to thissolution, and the resulting mixture was stirred at room temperature for24 hours. After the reaction was quenched with 10 mL of 1N hydrochloricacid, the resulting mixture was separated into layers, and extractionwas performed twice with 10 mL of ethyl acetate, followed by washing ofthe organic phases with 10 mL of 1% brine. Thereafter, ethyl acetate wasdistilled off under reduced pressure, and purification was performed bysilica gel chromatography (only ethyl acetate) to obtain 568.1 mg ofphosphonic acid ester compound (9a) (yield: 73%).

Synthesis Example G2-1 (Step G: Condensation Agent=DCC) Synthesis of9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of dichloromethane, and 510.1 mgof oleic acid was further added thereto. Subsequently, the solution wascooled to 0° C., and 447.2 mg of DCC was added thereto, followed bystirring at room temperature for 23 hours. The obtained white solid wasseparated by filtration, and washed with 3 mL of dichloromethane.Thereafter, the filtrate was concentrated under reduced pressure, andthe residue was purified with silica gel chromatography (only ethylacetate) to obtain 27.1 mg of phosphonic acid ester compound (9a)(yield: 3.5%).

Synthesis Example G2-2 (Step G: Condensation Agent=DCC, Additive=DMAP)Synthesis of 9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of dichloromethane. Then, 510.1mg of oleic acid and 66.2 mg of 4-DMAP were added thereto, followed bycooling to 0° C. Thereafter, 447.2 mg of DCC was added thereto, and themixture was stirred at room temperature for 2 hours. The obtained whitesolid was separated by filtration, and washed with 15 mL ofdichloromethane. Thereafter, the filtrate was concentrated under reducedpressure, and purification was performed by silica gel chromatography(only ethyl acetate) to obtain 458.0 mg of phosphonic acid estercompound (9a) (yield: 59%).

Synthesis Example G2-3 (Step G: Condensation Agent=DIC) Synthesis of9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of dichloromethane, and 510.1 mgof oleic acid was added thereto, followed by cooling to 0° C. Then, 339μL of DIC was added thereto, followed by stirring at room temperaturefor 3 days. The obtained white solid was separated by filtration, andwashed with 5 mL of dichloromethane. Thereafter, the filtrate wasconcentrated under reduced pressure, and purification was performed bysilica gel chromatography (only ethyl acetate) to obtain 137.8 mg ofphosphonic acid ester compound (9a) (yield: 18%).

Synthesis Example G2-4 (Step G: Condensation Agent=DIC, Additive=DMAP)Synthesis of 9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (5a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of dichloromethane. Then, 510.1mg of oleic acid and 66.2 mg of 4-DMAP were added thereto, followed bycooling to 0° C. Subsequently, 339 μL of DIC was added to this solution,followed by stirring at room temperature for 24 hours. The obtainedwhite solid was separated by filtration, and washed with 5 mL ofdichloromethane. Thereafter, the filtrate was concentrated under reducedpressure, and purification was performed by silica gel chromatography(only ethyl acetate) to obtain 569.9 mg of phosphonic acid estercompound (9a) (yield: 73%).

Synthesis Example G3-1 (Step G: Reaction Using Oleyl Chloride) Synthesisof 9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) obtained in Synthesis ExampleF1-1 (300.0 mg) was dissolved in 6.0 mL of dichloromethane, and 376 μLof triethylamine was added thereto, followed by cooling to 0° C. Then,717 UL of oleyl chloride was added thereto, followed by stirring at roomtemperature for 5.5 hours. After the reaction was quenched with 10 mL ofwater, extraction was performed twice with 10 mL of dichloromethane,followed by washing of the organic phases with 1% brine. Then,dichloromethane was distilled off under reduced pressure, andpurification was performed by silica gel chromatography (only ethylacetate) to obtain 658.4 mg of phosphonic acid ester compound (9a)(yield: 85%).

Synthesis Example G3-2 (Step G: Reaction Using Prepared Oleyl Chloride)Synthesis of 9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

Oleic acid (510.1 mg) was dissolved in 6.0 mL of toluene, and 7 μL ofN,N-dimethylformamide and 156 μL of thionyl chloride were added thereto,followed by stirring at 40° C. for 2 hours. Subsequently, toluene wasdistilled off under reduced pressure. Then, 5 mL of toluene was added,toluene was distilled off again under reduced pressure, and theresulting product was dissolved in 3.0 mL of dichloromethane.Separately, 300.0 mg of cyclic phosphonic acid compound (8a) wasdissolved in 3.0 mL of dichloromethane, and 376 μL of triethylamine wasfurther added thereto. After ice-cooling, the prepared oleyl chloride indichloromethane (3.0 mL) was added thereto dropwise, followed bystirring at room temperature for 3 hours. After the reaction wasquenched with 10 mL of water, extraction was performed twice with 10 mLof dichloromethane, and the organic phases were washed with 1% brine.Dichloromethane was distilled off under reduced pressure, andpurification was performed by silica gel chromatography (only ethylacetate) to obtain 571.2 mg of phosphonic acid ester compound (9a)(yield: 73%).

Synthesis Example G3-3 (Step G: Reaction Using Prepared Oleyl Chloride)Synthesis of 9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

Oleic acid (510.1 mg) was dissolved in 6.0 mL of toluene, and 7 μL ofN,N-dimethylformamide and 190 μL of oxalyl dichloride were addedthereto. The resulting mixture was stirred at 40° C. for 3.5 hours, andtoluene was distilled off under reduced pressure. Then, 5 mL of toluenewas added, toluene was distilled off again under reduced pressure, andthe resulting product was dissolved in 3.0 mL of dichloromethane.Separately, 300.0 mg of cyclic phosphonic acid compound (8a) wasdissolved in 3.0 mL of dichloromethane, 376 μL of triethylamine wasfurther added thereto, and after ice-cooling, the acid chloride preparedwith 3.0 mL of dichloromethane was added thereto dropwise, followed bystirring at room temperature for 2 hours. After the reaction wasquenched with 10 mL of water, extraction was performed twice with 10 mLof dichloromethane, and the organic phases were washed with 10 mL ofwater. Dichloromethane was distilled off under reduced pressure, andpurification was performed by silica gel chromatography (only ethylacetate) to obtain 515.6 mg of phosphonic acid ester compound (9a)(yield: 66%).

Synthesis Example G4-1 (Step G: Reaction Using p-ToluenesulfonylChloride) Synthesis of 9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

Oleic acid (510.1 mg) was dissolved in 3.0 mL of dichloromethane, and430 μL of N-methylimidazole (NMM) was further added thereto. Aftercooling to 0° C., the resulting mixture was stirred at 0° C. for 1 hour.Subsequently, 3.0 mL of a solution of 300.0 mg of cyclic phosphonic acidcompound (8a) in dichloromethane was added thereto dropwise, followed bystirring at 0° C. for 1.5 hours. After the reaction was quenched with 10mL of water, extraction was performed twice with 10 mL ofdichloromethane, and the organic phases were washed with 1% brine.Dichloromethane was distilled off under reduced pressure, andpurification was performed by silica gel chromatography (only ethylacetate) to obtain 603.8 mg of phosphonic acid ester compound (9a)(yield: 78%).

Synthesis Example G4-2 (Step G: Reaction Using Mukaiyama Reagent)Synthesis of 9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) (421.9 mg) and oleic acid(717.4 mg) were dissolved in 8.5 mL of dichloromethane. Then, 845 μL oftriethylamine and 778.7 mg of 2-chloro-1-methylpyridinium iodide (CMPI)were further added thereto, followed by heating under reflux for 3hours. After the reaction was quenched with 10 mL of water, extractionwas performed twice with 10 mL of dichloromethane. Dichloromethane wasdistilled off under reduced pressure, and purification was performed bysilica gel chromatography (only ethyl acetate) to obtain 263.8 mg ofphosphonic acid ester compound (9a) (yield: 34%).

Synthesis Example G4-3 (Step G: Reaction Using pyBop) Synthesis of9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) (200.0 mg) and oleic acid(340.1 mg) were dissolved in 4.0 mL of dichloromethane, followed byaddition of 420 μL of diisopropylethylamine. After ice-cooling, 752 mgof pyBop was added thereto, and the mixture was stirred at roomtemperature for 6 hours. After the reaction was quenched with 5 mL of 1N hydrochloric acid, extraction was performed twice with 10 mL and 5 mLof dichloromethane, and the organic phases were washed with 10 mL ofwater. Dichloromethane was distilled off under reduced pressure, andpurification was performed by silica gel chromatography (only ethylacetate) to obtain 513.8 mg of phosphonic acid ester compound (9a)(yield: 99%).

Synthesis Example G4-4 (Step G: Reaction Using HATU) Synthesis of9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) (300.0 mg) and oleic acid(510.1 mg) were dissolved in 6.0 mL of dichloromethane, and 630 μL ofdiisopropylethylamine was further added thereto. After ice-cooling,824.0 mg of HATU was added thereto, and the mixture was stirred at roomtemperature for 24 hours. After the reaction was quenched with 10 mL of1 N hydrochloric acid, extraction was performed twice with 10 mL ofdichloromethane, and the organic phases were washed with 10 mL of water.Dichloromethane was distilled off under reduced pressure, andpurification was performed by silica gel chromatography (only ethylacetate) to obtain 513.2 mg of phosphonic acid ester compound (9a)(yield: 68%).

Synthesis Example G4-5 (Step G: Reaction Using HBTU) Synthesis of9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (5a) (300.0 mg) and oleic acid(510.1 mg) was dissolved in 6.0 mL of dichloromethane, and 630 μL ofdiisopropylethylamine was further added thereto. After ice-cooling,822.0 mg of HBTU was added thereto, and the mixture was stirred at roomtemperature for 6.5 hours. After the reaction was quenched with 10 mL of1N hydrochloric acid, extraction was performed twice with 10 mL ofdichloromethane, and the organic phases were washed with 10 mL of water.Dichloromethane was distilled off under reduced pressure, andpurification was performed by silica gel chromatography (only ethylacetate) to obtain 612.0 mg of phosphonic acid ester compound (9a)(yield: 79%).

Synthesis Example G4-6 (Step G: Reaction Using COMU) Synthesis of9-octadecenoic acid(9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

The cyclic phosphonic acid compound (8a) (300.0 mg) and oleic acid(510.1 mg) were dissolved in 6.0 mL of dichloromethane, and 630 μL ofdiisopropylethylamine was further added thereto. After ice-cooling,928.1 mg of COMU was added thereto, and the mixture was stirred at roomtemperature for 24 hours. Subsequently, the reaction was quenched with10 mL of 1 N hydrochloric acid, extraction was performed twice with 10mL of dichloromethane, and the organic phases were washed with 10 mL ofwater. Dichloromethane was distilled off under reduced pressure, andpurification was performed by silica gel chromatography (only ethylacetate) to quantitatively obtain 778.2 mg of phosphonic acid estercompound (9a).

Synthesis Example G5 (Telescoping Method) Synthesis of 9-octadecenoicacid (9Z)-(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester (9a)

Step B

The compound (3a) (30.0 g) was dissolved in 456 mL of CH₂Cl₂, and 42.7mL of triethylamine was added thereto, followed by cooling to −20° C.Then, 19.1 mL of MsCl was added thereto, and the resulting mixture wasstirred at −2° C. for 1 hour. The reaction was stopped with 250 mL ofwater, and the layers were separated, after which the water layer wasextracted with 150 mL of CH₂Cl₂, and the organic layer was washed with200 mL of water.

Step C

The organic layer was concentrated under reduced pressure, and theobtained residue was dissolved in 684 mL of methyl ethyl ketone. Then,1.42 mL of triethylamine and 46.14 g of sodium iodide were addedthereto, and the mixture was allowed to react under heating at refluxfor 2.5 hours. After the reaction solution was cooled, methyl ethylketone was distilled off under reduced pressure, 300 mL of CH₂Cl₂ and300 mL of water were added thereto, and the resulting mixture wasseparated into layers. After the water layer was extracted twice with150 mL of of CH₂Cl₂, the organic layers were washed with 2.5% sodiumthiosulfate and 300 mL of 0.5% sodium bicarbonate water. The resultingproduct was then separated into layers and washed with 300 mL of water,and the organic layer was concentrated under reduced pressure.

Step D

The resulting residue was dissolved in 410 mL of DMF. Then, 133.73 g ofcesium carbonate and 37.64 mL of dimethyl phosphite were added thereto,and the mixture was allowed to react at 50° C. for 3 hours. DMF in thereaction solution was distilled off under reduced pressure, 300 mL oftoluene was added thereto, and a white solid was filtered.

Step E

After the white solid was washed with 150 mL of toluene, the filtratewas concentrated under reduced pressure, and the resulting residue wasdissolved in 410 mL of methanol. Then, 1.95 g of p-toluenesulfonic acidmonohydrate was added to this solution, and the resulting mixture wasstirred at 20° C. for 2 hours.

Step F

The reaction solution was concentrated under reduced pressure, and theresulting residue was dissolved in 821 mL of DMF. Then, 9.21 mL of DBUwas added thereto, and the resulting mixture was stirred at 20° C. for 3hours. Further, 11.71 g of p-toluenesulfonic acid monohydrate was addedto this solution to stop the reaction, and DMF was distilled off underreduced pressure.

Step G

The resulting residue was dissolved in 684 mL of CH₂Cl₂. Then, 57.97 gof oleic acid, 7.52 g of DMAP, and 47.21 g of EDC were further addedthereto, and the mixture was allowed to react at 20° C. for 12 hours.Subsequently, 300 mL of 1 N hydrochloric acid was added thereto, and theresulting mixture was separated into layers. The water layer wasextracted twice with 300 mL of CH₂Cl₂, and the organic layers werewashed with 300 mL of water and then concentrated. The resulting residuewas purified with silica gel chromatography (eluted only with ethylacetate) to obtain 61.99 g of compound (9a) (yield: 70%) (all steps).

Step (H) Example 1 Production of 2ccPA Crystal (Good Solvent: Water,Poor Solvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of Synthesis Example G5 was dissolved in 11.6 mL of methyl ethylketone. Then, 522.3 mg of sodium iodide was added thereto, and themixture was allowed to react under heating at reflux for 14 hours. Afterthe reaction, the reaction solution was concentrated and then dissolvedat 60° C. in 5 mL of water, followed by cooling to 20° C. Thereafter, 20mL of acetone was added to this solution dropwise, and the mixture wasaged for 1 hour. The resulting crystal was filtered, washed with 30 mLof acetone, and dried under reduced pressure to obtain 651.0 mg of 2ccPAwith a purity of 98.874%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. The X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 16.1724 98 9.6675 284.9186 21 4.8335 23 4.5164 100 4.1835 14 3.7921 10 IR spectrum (cm⁻¹):2920, 2851, 1728, 1204, 1176, 1098, 1012, 774, 744, 721 Melting point:189° C.

Example 2 Production of 2ccPA Crystal (Good Solvent: Methanol, PoorSolvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 13 hours. After the reaction, thereaction solution was concentrated and dissolved at 40° C. in 2.5 mL ofmethanol, followed by cooling to 10° C. Subsequently, 2.5 mL of acetonewas added to this solution dropwise. After the temperature was increasedto 20° C., 7.5 mL of acetone was added thereto dropwise, and the mixturewas aged for 1 hour. Thereafter, the resulting crystal was filtered,washed with 30 mL of acetone, and dried under reduced pressure to obtain907.6 mg of 2ccPA with a purity of 98.880%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9390 100 9.5838 234.9294 22 4.7972 18 4.4982 95 4.1913 19 3.7953 9 IR spectrum (cm⁻¹):2920, 2851, 1733, 1209, 1166, 1097, 1013, 774, 738, 722 Melting point:188° C.

Example 3 Production of 2ccPA Crystal (Good Solvent: Methanol, PoorSolvent: Methyl Ethyl Ketone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 13 hours. After the reaction, thereaction solution was concentrated and dissolved at 40° C. in 2.5 mL ofmethanol, followed by cooling to 10° C. Subsequently, 2.5 mL of methylethyl ketone was added to this solution dropwise. After the temperaturewas increased to 20° C., 7.5 mL of methyl ethyl ketone was addedthereto, and the mixture was aged for 1 hour. Thereafter, the resultingcrystal was filtered, washed with 30 mL of methyl ethyl ketone, anddried under reduced pressure to obtain 862.8 mg of 2ccPA with a purityof 98.944%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.8817 92 9.5631 224.9186 24 4.7869 20 4.4937 100 4.1835 19 3.7794 9 IR spectrum (cm⁻¹):2920, 2851, 1727, 1205, 1175, 1099, 1024, 773, 742, 721 Melting point:187° C.

Example 4 Production of 2ccPA Crystal (Good Solvent: Methanol, PoorSolvent: Methyl Isobutyl Ketone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 12 hours. After the reaction, thereaction solution was concentrated and dissolved at 40° C. in 2.5 mL ofmethanol, followed by cooling to 10° C. Subsequently, 2.5 mL of methylisobutyl ketone was added to this solution dropwise. After thetemperature was increased to 20° C., 7.5 mL of methyl isobutyl ketonewas added thereto dropwise, and the mixture was aged for 1 hour.Thereafter, the resulting crystal was filtered, washed with 30 mL ofmethyl isobutyl ketone, and dried under reduced pressure to obtain 819.1mg of 2ccPA with a purity of 99.300%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.8817 100 9.5631 234.9294 10 4.7920 10 4.4982 44 4.1874 10 3.8017 5 IR spectrum (cm⁻¹):2920, 2851, 1735, 1210, 1165, 1096, 1012, 776, 738, 722 Melting point:189° C.

Example 5 Production of 2ccPA Crystal (Good Solvent: Methanol, PoorSolvent: Methyl Ethyl Ketone:Acetone=1:1)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto and allowed to react underheating at reflux for 13.5 hours. After the reaction, the reactionsolution was concentrated and then dissolved at 40° C. in 2.5 mL ofmethanol, followed by cooling to 10° C. Thereafter, 2.5 mL of a liquidmixture of acetone and methyl ethyl ketone was added to this solutiondropwise. After the temperature was increased to 20° C., 7.5 mL of aliquid mixture of acetone and methyl ethyl ketone was added theretodropwise, and the mixture was aged for 1 hour. Thereafter, the resultingcrystal was filtered, washed with 30 mL of a liquid mixture of acetoneand methyl ethyl ketone, and dried under reduced pressure to obtain853.8 mg of 2ccPA with a purity of 98.880%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.8817 100 9.5631 234.9186 14 4.7869 13 4.4937 57 4.1874 14 3.7921 7 IR spectrum (cm⁻¹):2920, 2851, 1733, 1209, 1166, 1097, 1013, 775, 738, 722

Example 6 Production of 2ccPA Crystal (Good Solvent: Ethanol,Crystallization Temperature: 10° C.)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 13 hours. After the reaction, thereaction solution was concentrated and dissolved at 60° C. in 7.5 mL ofethanol. The resulting mixture was cooled to 10° C. and aged for 1 hour.Thereafter, the resulting crystal was filtered, washed with 30 mL ofacetone, and dried under reduced pressure to obtain 846.6 mg of 2ccPAwith a purity of 98.890%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.8248 100 9.5425 244.9078 18 4.7920 17 4.4937 78 4.1796 15 3.7762 8 IR spectrum (cm⁻¹):2920, 2851, 1728, 1207, 1167, 1097, 1013, 774, 741, 721 Melting point:189° C.

Example 7 Production of 2ccPA Crystal (Good Solvent: Ethanol,Crystallization Temperature: 20° C.)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 16 hours. After the reaction, thereaction solution was concentrated and dissolved at 65° C. in 6 mL ofethanol. The resulting mixture was cooled to 20° C. and aged for 1 hour.Thereafter, the resulting crystal was filtered, washed with 30 mL ofacetone, and dried under reduced pressure to obtain 783.3 mg of 2ccPAwith a purity of 98.997%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 16.0548 100 9.6046 244.9294 7 4.8075 9 4.5073 29 4.2070 7 3.7857 4 IR spectrum (cm⁻¹): 2920,2851, 1728, 1211, 1175, 1096, 1013, 775, 745, 722 Melting point: 190° C.

Example 8 Production of 2ccPA Crystal (Good Solvent: Ethanol, PoorSolvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 13 hours. After the reaction, thereaction solution was concentrated and then dissolved at 60° C. in 6 mLof ethanol, followed by cooling to 20° C. After 6 mL of acetone wasadded to this solution dropwise, the mixture was aged for 2 hours.Thereafter, the resulting crystal was filtered, washed with 30 mL ofacetone, and dried under reduced pressure to obtain 786.4 mg of 2ccPAwith a purity of 99.054%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9967 100 9.6046 244.9349 19 4.8023 17 4.5073 76 4.1913 13 3.8017 7 IR spectrum (cm⁻¹):2920, 2851, 1727, 1212, 1172, 1096, 1024, 776, 746, 721 Melting point:189° C.

Example 9 Production of 2ccPA Crystal (Good Solvent:Methanol:Ethanol=1:1, Poor Solvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 13.5 hours. After the reaction, thereaction solution was concentrated, dissolved at 60° C. in 2.5 mL of aliquid mixture of methanol and ethanol, and cooled to 10° C. After 2.5mL of acetone was added thereto dropwise, the temperature was increasedto 20° C., 7.5 mL of acetone was added thereto dropwise, and the mixturewas aged for 1 hour. The resulting crystal was filtered, washed with 30mL of acetone, and dried under reduced pressure to obtain 954.2 mg of2ccPA with a purity of 98.812%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.8817 100 9.5631 244.9294 8 4.7920 8 4.4982 37 4.1913 10 3.8017 5 IR spectrum (cm⁻¹): 2920,2851, 1734, 1210, 1165, 1097, 1012, 775, 738, 722 Melting point: 189° C.

Example 10 Production of 2ccPA Crystal (Good Solvent: 1-Propanol,Crystallization Temperature: 10° C.)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 13 hours. After the reaction, thereaction solution was concentrated and dissolved at 60° C. in 7.5 mL of1-propanol. The resulting mixture was cooled to 10° C. and aged for 1hour. Subsequently, the resulting crystal was filtered, washed with 70mL of acetone, and dried under reduced pressure to obtain 645.0 mg of2ccPA with a purity of 98.419%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9967 100 9.6046 244.9024 7 4.8075 12 4.5027 32 4.1835 7 3.7636 6 IR spectrum (cm⁻¹): 2920,2851, 1727, 1207, 1170, 1098, 1014, 774, 745, 721 Melting point: 190° C.

Example 11 Production of 2ccPA Crystal (Good Solvent: 1-Propanol,Crystallization Temperature: 20° C.)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 14 hours. After the reaction, thereaction solution was concentrated and dissolved at 50° C. in 6.0 mL of1-propanol. The resulting mixture was cooled to 20° C. and aged for 1hour. Thereafter, the resulting crystal was filtered, washed with 30 mLof acetone, and dried under reduced pressure to obtain 866.5 mg of 2ccPAwith a purity of 98.750%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 16.0548 100 9.6255 244.9403 11 4.8023 12 4.5073 51 4.1992 11 3.7985 6 IR spectrum (cm⁻¹):2920, 2851, 1727, 1205, 1174, 1098, 1023, 773, 743, 721 Melting point:188° C.

Example 12 Production of 2ccPA Crystal (Good Solvent: 1-Propanol, PoorSolvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 15.5 hours. After the reaction, thereaction solution was concentrated and dissolved at 60° C. in 6.0 mL of1-propanol, followed by cooling to 20° C. Then, 6.0 mL of acetone wasadded to this solution dropwise, and the mixture was aged at 20° C. for1 hour. Thereafter, the resulting crystal was filtered, washed with 30mL of acetone, and dried under reduced pressure to obtain 866.9 mg of2ccPA with a purity of 98.902%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 16.0548 100 9.6255 234.9349 9 4.8075 10 4.5073 35 4.1952 7 3.7857 4 IR spectrum (cm⁻¹): 2920,2851, 1727, 1206, 1175, 1097, 1023, 774, 744, 721 Melting point: 187° C.

Example 13 Production of 2ccPA Crystal (Good Solvent: Isopropyl Alcohol,Crystallization Temperature: 20° C.)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 15 hours. After the reaction, thereaction solution was concentrated and dissolved at 65° C. in 6.0 mL of1-propanol. The resulting mixture was cooled to 20° C. and aged for 1hour. Thereafter, the resulting crystal was filtered, washed with 30 mLof acetone, and dried under reduced pressure to obtain 942.2 mg of 2ccPAwith a purity of 98.588%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9390 80 9.5631 204.9186 26 4.7972 21 4.4982 100 4.1874 17 3.7953 9 IR spectrum (cm⁻¹):2920, 2851, 1727, 1212, 1175, 1095, 1023, 776, 746, 722 Melting point:188° C.

Example 14 Production of 2ccPA Crystal (Good Solvent: Isopropyl Alcohol,Poor Solvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 14 hours. After the reaction, thereaction solution was concentrated and dissolved at 60° C. in 6.0 mL ofisopropyl alcohol, followed by cooling to 20° C. Then, 6.0 mL of acetonewas added to this solution dropwise, and the mixture was aged at 20° C.for 1 hour. Thereafter, the resulting crystal was filtered, washed with30 mL of acetone, and dried under reduced pressure to obtain 915.8 mg of2ccPA with a purity of 98.761%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.939 86 9.5838 214.9132 25 4.7920 21 4.4937 100 4.1874 17 3.7762 8 IR spectrum (cm⁻¹):2921, 2851, 1727, 1212, 1175, 1095, 1023, 776, 745, 722 Melting point:187° C.

Example 15 Production of 2ccPA Crystal (Good Solvent: 1-Butanol, PoorSolvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 12 hours. After the reaction, thereaction solution was concentrated and dissolved at 65° C. in 6.0 mL of1-butanol, followed by cooling to 20° C. Then, 6.0 mL of acetone wasadded to this solution dropwise, and the mixture was aged at 20° C. for3.5 hours. Thereafter, the resulting crystal was filtered, washed with30 mL of acetone, and dried under reduced pressure to obtain 598.9 mg of2ccPA with a purity of 98.773%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9967 100 9.6046 254.9024 8 4.8075 12 4.4982 36 4.1719 7 3.7293 6 IR spectrum (cm⁻¹): 2920,2851, 1728, 1206, 1175, 1097, 1013, 774, 745, 721 Melting point: 189° C.

Example 16 Production of 2ccPA Crystal (Reaction Solvent and aCrystallization Solvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of acetone. Then, 522.3 mg ofsodium iodide was added thereto, and the mixture was allowed to reactunder heating at reflux for 48 hours. After cooling to room temperature,the resulting crystal was filtered, washed with 30 mL of acetone, anddried under reduced pressure to obtain 898.0 mg of 2ccPA with a purityof 86.921%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 16.0548 100 9.6255 234.9349 27 4.8075 21 4.5073 99 4.1992 15 3.8145 8 IR spectrum (cm⁻¹) :2920, 2851, 1727, 1211, 1175, 1095, 1023, 776, 746, 722 Melting point:189° C.

Example 17 Production of 2ccPA Crystal (Reaction Solvent andCrystallization Solvent: Methyl Ethyl Ketone, Poor Solvent: Acetone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of acetone. Then, 522.3 mg ofsodium iodide was added thereto, and the mixture was allowed to reactunder heating at reflux for 15 hours. After cooling to room temperature,11.6 mL of acetone was added thereto dropwise, and the resulting crystalwas filtered, washed with 30 mL of acetone, and dried under reducedpressure to obtain 950.7 mg of 2ccPA with a purity of 98.429%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.7684 67 9.5425 164.8282 27 4.4802 100 4.1757 16 3.7263 10 IR spectrum (cm⁻¹): 2920, 2851,1727, 1211, 1175, 1096, 1015, 775, 744, 722 Melting point: 189° C.

Example 18 Production of 2ccPA Crystal (Reaction Solvent andCrystallization Solvent: Methyl Isobutyl Ketone)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of acetone. Then, 522.3 mg ofsodium iodide was added thereto, and the mixture was allowed to reactunder heating at reflux for 6 hours. After cooling to 10° C. and agingfor 1 hour, the resulting crystal was filtered, washed with 30 mL ofacetone, and dried under reduced pressure to obtain 950.7 mg of 2ccPAwith a purity of 20.777%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9390 100 9.5838 264.9132 6 4.8023 8 4.4937 23 4.1641 6 3.7730 4 IR spectrum (cm⁻¹): 2921,2852, 1731, 1208, 1174, 1094, 1011, 778, 745, 722 Melting point: 187° C.

Example 19 Production of 2ccPA Crystal (Good Solvent: Methanol, PoorSolvent: Ethyl Acetate)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 13 hours. After the reaction, thereaction solution was concentrated and dissolved at 40° C. in 2.5 mL ofmethanol, followed by cooling to 10° C. Thereafter, 2.5 mL of ethylacetate was added thereto dropwise. After the temperature was increasedto 20° C., 7.5 mL of ethyl acetate was added dropwise, and the mixturewas aged for 1 hour. Thereafter, the resulting crystal was filtered,washed with 30 mL of ethyl acetate, and dried under reduced pressure toobtain 719.8 mg of 2ccPA with a purity of 98.204%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9390 100 9.5838 224.9186 16 4.7920 13 4.4937 62 4.1835 13 3.7921 7 IR spectrum (cm⁻¹):2920, 2851, 1728, 1208, 1166, 1097, 1013, 773, 738, 722 Melting point:190° C.

Example 20 Production of 2ccPA Crystal (Good Solvent: Methanol, PoorSolvent: Butyl Acetate)

The cyclic phosphonic acid ester (9a) (1.0 g) obtained by the productionmethod of G5 was dissolved in 11.6 mL of methyl ethyl ketone. Then,522.3 mg of sodium iodide was added thereto, and the mixture was allowedto react under heating at reflux for 13 hours. After the reaction, thereaction solution was concentrated and dissolved at 40° C. in 2.5 mL ofmethanol, followed by cooling to 10° C. Thereafter, 2.5 mL of butylacetate was added thereto dropwise. After the temperature was increasedto 20° C., 7.5 mL of butyl acetate was added dropwise, and the mixturewas aged for 1 hour. Then, the resulting crystal was filtered, washedwith 30 mL of butyl acetate, and dried under reduced pressure to obtain548.0 mg of 2ccPA with a purity of 98.350%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9390 100 9.5838 234.9240 9 4.7920 9 4.4982 36 4.1874 9 3.7921 5 IR spectrum (cm⁻¹): 2920,2851, 1735, 1210, 1165, 1097, 1012, 776, 738, 722 Melting point: 189° C.

Example 21 Repurification of 2ccPA (Good Solvent: Methanol, PoorSolvent: Methyl Ethyl Ketone)

The 2ccPA (3.00 g) obtained in Example 2 was dissolved at 40° C. in 7.3mL of methanol, and the solution was cooled to 10° C. After 1 hour ofstirring, 7.3 mL of methyl ethyl ketone was added thereto dropwise.Thereafter, the temperature was increased to 20° C., and 22 mL of methylethyl ketone was added thereto dropwise again. After 1 hour of aging at20° C., the resulting crystal was filtered and washed with 36 mL ofmethyl ethyl ketone to obtain 2.55 g of 2ccPA with a purity of 99.511%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 16.0548 100 9.6255 244.9186 14 4.7920 14 4.4982 67 4.1835 14 3.7985 8 IR spectrum (cm⁻¹):2920, 2851, 1735, 1210, 1165, 1096, 1012, 776, 738, 722 Melting point:189° C.

Example 22 Repurification of 2ccPA (Good Solvent: Methanol, PoorSolvent: Ethyl Acetate)

The 2ccPA (3.00 g) obtained in Example 2 was dissolved at 40° C. in 7.3mL of methanol, and the solution was cooled to 10° C. After 1 hour ofstirring, 7.3 mL of ethyl acetate was added thereto dropwise.Thereafter, the temperature was increased to 20° C., 22 mL of ethylacetate was added thereto dropwise again, and the mixture was aged at20° C. for 1 hour. Subsequently, the resulting crystal was filtered andwashed with 36 mL of ethyl acetate to obtain 2.52 g of 2ccPA with apurity of 99.610%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 16.0548 100 9.6255 244.9294 17 4.7972 15 4.5073 74 4.1874 15 3.7985 8 IR spectrum (cm⁻¹):2920, 2851, 1735, 1210, 1165, 1097, 1012, 776, 738, 722 Melting point:187° C.

Example 23 Repurification of 2ccPA (Good Solvent: Methanol, PoorSolvent: 1-Propanol)

The 2ccPA (3.00 g) obtained in Example 2 was dissolved at 40° C. in 7.3mL of methanol, and the solution was cooled to 10° C. After 1 hour ofstirring, 7.3 mL of 1-propanol was added thereto dropwise. Thereafter,the temperature was increased to 20° C., 22 mL of 1-propanol was addeddropwise again, and the mixture was aged at 20° C. for 1 hour.Subsequently, the resulting crystal was filtered and washed with 36 mLof 1-propanol to obtain 1.67 g of 2ccPA with a purity of 99.628%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 16.0548 100 9.6255 244.9186 15 4.8075 15 4.4982 67 4.1835 13 3.8049 7 IR spectrum (cm⁻¹):2920, 2851, 1734, 1210, 1166, 1097, 1012, 775, 738, 722 Melting point:187° C.

Example 24 Repurification of 2ccPA (Good Solvent: Methanol, PoorSolvent: Methyl Acetate)

The 2ccPA (3.00 g) obtained in Example 2 was dissolved at 40° C. in 7.3mL of methanol, and the solution was cooled to 10° C. After 1 hour ofstirring, 7.3 mL of methyl acetate was added thereto dropwise.Thereafter, the temperature was increased to 20° C., 22 mL of methylacetate was added dropwise again, and the mixture was aged at 20° C. for1 hour. Subsequently, the resulting crystal was filtered and washed with36 mL of methyl acetate to obtain 2.49 g of 2ccPA with a purity of99.559%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9967 100 9.6046 234.9240 11 4.8023 10 4.4982 44 4.1874 10 3.7985 5 IR spectrum (cm⁻¹):2920, 2851, 1735, 1210, 1165, 1097, 1012, 776, 738, 722 Melting point:189° C.

Example 25 Repurification of 2ccPA (Good Solvent: Methanol, PoorSolvent: Isopropyl Acetate)

The 2ccPA (3.00 g) obtained in Example 2 was dissolved at 40° C. in 7.3mL of methanol, and the solution was cooled to 10° C. After 1 hour ofstirring, 7.3 mL of isopropyl acetate was added thereto dropwise.Thereafter, the temperature was increased to 20° C., 22 mL of isopropylacetate was added dropwise again, and the mixture was aged at 20° C. for1 hour. Subsequently, the resulting crystal was filtered and washed with36 mL of isopropyl acetate to obtain 2.37 g of 2ccPA with a purity of99.549%.

The following shows the X-ray powder diffraction spectrum of theobtained 2ccPA white crystal. This X-ray powder diffraction spectrum wasobtained by copper radiation of λ=1.54059 Å through a monochromator.

d (Interplanar spacing) Relative intensity (I/I₀) 15.9390 100 9.5838 224.9186 10 4.7869 10 4.4937 45 4.1796 10 3.7985 5 IR spectrum (cm⁻¹):2920, 2851, 1735, 1210, 1165, 1097, 1012, 776, 738, 722 Melting point:187° C.

Example 26 (Synthesis of 2ccPA—Reaction Solvent: Acetone)

The cyclic phosphonic acid ester compound (9a) (200 mg) was dissolved in2.3 mL of acetone. Then, 104.5 mg of sodium iodide was added thereto,and the mixture was allowed to react under heating at reflux for 23hours. After cooling to 20° C., the generated white solid was filtered.The resulting crystal was washed with acetone to thus obtain 174.2 mg ofwhite crystal of 2ccPA (1) (melting point of 189.6° C.).

¹H-NMR (500 MHz, CDCl₃)

δ: 0.79 (t, J=6.5 Hz), 1.19-1.23 (m, 20H), 1.36 (m, 1H), 1.51 (br, 2H),1.79 (m, 1H), 1.93 (br, 4H), 2.26 (t, J=7.5 Hz, 2H), 2.72 (m, 1H),3.65-4.10 (m, 4H), 5.20-5.28 (m, 2H)

Synthesis Study According to a Formulation Described in DocumentsComparative Example 1: Synthesis of Phosphonic Acid Dimethyl Ester,Arbuzov Reaction

The iodine compound (5a) (15.00 g) was dissolved in 105 mL of trimethylphosphite, followed by heating under reflux for 14 hours. Then, 210 mLof trimethyl phosphite was added again, and the mixture was heated underreflux for 6 hours. After concentration, the resulting residue waspurified with silica gel chromatography (chloroform:methanol=15:1) toobtain 8.34 g of phosphonic acid dimethyl compound (6a) (yield: 60%),which contained by-products with an unknown structure.

Comparative Example 2: Synthesis of(2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methanol, cyclizationreaction

The phosphonic acid dimethyl compound (6a) (8.34 g) obtained inComparative Example 1 was dissolved in 417 mL of toluene and 14.1 mL ofmethanol. Then, 1.53 g of p-toluenesulfonic acid monohydrate was addedthereto, and the mixture was heated under reflux for 3 hours. Tolueneand methanol were then distilled off under reduced pressure, and silicagel chromatography (chloroform:methanol=15:1) was carried out to obtain2.44 g of cyclic phosphonic acid compound (8a) (yield: 42%).

Comparative Example 3: Synthesis of (9-octadecenoicacid-2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl ester,Condensation Reaction

The cyclic phosphonic acid compound (8a) (2.42 g) obtained inComparative Example 2, 4.11 g of oleic acid, and 534.0 mg of4-dimethylaminopyridine were dissolved in 48.6 mL of dichloromethane.After the resulting mixture was ice-cooled, 3.35 g of EDC, 1.23 g ofoleic acid, 2.23 g of EDC, and 808 mL of dichloromethane were addedthereto, followed by stirring at room temperature for 24 hours. Theresulting product was diluted with 571 mL of methanol, and 300 mL ofwater was added thereto. After the layers were separated, the waterphase was extracted twice with 300 mL and 100 mL of ethyl acetate, theorganic phases were dried over magnesium sulfate, and ethyl acetate andmethanol were distilled off under reduced pressure. The resultingresidue was purified with silica gel chromatography (only with ethylacetate) to obtain 2.65 g of cyclic phosphonic acid ester compound (9a)(yield: 42%).

Comparative Example 4: Synthesis of (9-octadecenoicacid-2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester ProtonType, Demethylation Reaction

The cyclic phosphonic acid ester compound (9a) (2.51 g) synthesized inComparative Example 3 was dissolved in 303 mL of dichloromethane. Aftercooling to −15° C., 2.31 mL of bromo trimethylsilane was added thereto,and the mixture was stirred at −15° C. for 4.5 hours. The reactionsolution was poured into 200 mL of ice water, and extracted with 750 mLof diethyl ether. After the layers were separated, extraction wasperformed again twice with 200 mL of diethyl ether. The organic phaseswere dried over sodium sulfate, and the solvent was distilled off underreduced pressure. Thereafter, silica gel chromatography(chloroform:methanol=5:1) was carried out to obtain 367.6 mg of compound(10a: proton type of 2ccPA) (yield: 15%).

Comparative Example 5: Synthesis of (9-octadecenoicacid-2-methoxy-2-oxo-2λ⁵-[1,2]oxaphosphoran-4-yl)methyl Ester SodiumSalt

The compound (10a) obtained in Comparative Example 4 (418.6 mg) wasdissolved in 30 mL of diethyl ether. Then, 20 mL of 0.05 M aqueoussodium hydroxide solution was added thereto, and the mixture wasstirred. After the resulting mixture was separated into layers, thewater phase was freeze-dried to obtain 250.8 mg of 2ccPA (1) (yield:517%; purity: 67.934%).

Test Example 1: Stability Test at 35° C.

The 2ccPA crystal obtained in Example 3 (present invention), the 2ccPAobtained in Comparative Example 5 (a formula described in documents),and an amorphous of 2ccPA were individually stored at 35° C. for onemonth, and a stability test was performed. Table 1 below shows theresults.

As the amorphous of 2ccPA above, 300 mg of 2ccPA (obtained in Example 3)dissolved in 5 mL of water and freeze-dried was used.

In the stability test, about 15 mg each of the 2ccPA crystal of thepresent invention, the 2ccPA of a formula described in documents, and anamorphous of 2ccPA were weighed, and individually diluted with 5 mL ofacetonitrile/water (1/1). Then, 5 μL each of the diluted solutions wasanalyzed weekly using the LC-2010CHT (Shimazu Corporation).

TABLE 1 Number of days 0 7 14 21 28 42 56 A formula described indocuments 67.934% 66.665% 67.517% 62.77% 59.841% 2ccPA crystal of thepresent 99.561% 99.605% 99.576% 99.631% 99.626% 99.593% 99.493%invention Amorphous of 2ccPA 99.599% 83.363% 45.02% 34.738% 27.077%

As shown in the results in Table 1, the 2ccPA produced in accordancewith a formula described in documents in Comparative Examples 1 to 5 hadinsufficient purity and were unstable. Although the amorphous of 2ccPAhad satisfactory purity, decomposition proceeded each week, and thestability was unsatisfactory.

In contrast, the 2ccPA crystal obtained by the production method of thepresent invention had high purity and excellent stability. Even 56 dayslater, a purity as high as 99.493% was maintained; thus, the crystal ofthe present invention had excellent storage stability, compared to 2ccPAobtained by known production methods.

The invention claimed is:
 1. A crystal of a cyclic phosphonic acidsodium salt (2ccPA) represented by formula (1):


2. The crystal according to claim 1, having an X-ray powder diffractionspectrum comprising a characteristic peak expressed in degrees 2θ at 15°to 17°.
 3. The crystal according to claim 1, having an X-ray powderdiffraction spectrum comprising a characteristic peak expressed indegrees 2θ at 9° to 10°.
 4. The crystal according to claim 1, having anX-ray powder diffraction spectrum comprising characteristic peaksexpressed in degrees 2θ at 3° to 5°.
 5. The crystal according to claim1, having an X-ray powder diffraction spectrum obtained withmonochromated copper radiation of λ=1.54059 Å comprising a highestintensity at lattice spacing (d) of 15.7684 to 16.1724.
 6. The crystalaccording to claim 1, having an X-ray powder diffraction spectrumobtained with monochromated copper radiation of λ=1.54059 Å comprising acharacteristic peak at lattice spacing (d) of 15.7684 to 16.1724.
 7. Thecrystal according to claim 1, having an X-ray powder diffractionspectrum obtained with monochromated copper radiation of λ=1.54059 Åcomprising characteristic peaks at the following lattice spacings (d):15.7684 to 16.1724 9.5425 to 9.6675 4.9024 to 4.9403 4.7869 to 4.83354.4802 to 4.5164 4.1641 to 4.2070 3.7263 to 3.8145.
 8. The crystalaccording to claim 1, having an X-ray powder diffraction spectrumobtained with monochromated copper radiation of λ=1.54059 Å with latticespacing (d) satisfying any one of the requirements (a) to (y): (a)Lattice spacing (d) 16.1724 9.6675 4.9186 4.8335 4.5164 4.1835 3.7921(b) Lattice spacing (d) 15.9390 9.5838 4.9294 4.7972 4.4982 4.19133.7953 (c) Lattice spacing (d) 15.8817 9.5631 4.9186 4.7869 4.49374.1835 3.7794 (d) Lattice spacing (d) 15.8817 9.5631 4.9294 4.79204.4982 4.1874 3.8017 (e) Lattice spacing (d) 15.8817 9.5631 4.91864.7869 4.4937 4.1874 3.7921 (f) Lattice spacing (d) 15.8248 9.54254.9078 4.7920 4.4937 4.1796 3.7762 (g) Lattice spacing (d) 16.05489.6046 4.9294 4.8075 4.5073 4.2070 3.7857 (h) Lattice spacing (d)15.9967 9.6046 4.9349 4.8023 4.5073 4.1913 3.8017 (i) Lattice spacing(d) 15.8817 9.5631 4.9294 4.7920 4.4982 4.1913 3.8017 (j) Latticespacing (d) 15.9967 9.6046 4.9024 4.8075 4.5027 4.1835 3.7636 (k)Lattice spacing (d) 16.0548 9.6255 4.9403 4.8023 4.5073 4.1992 3.7985(l) Lattice spacing (d) 16.0548 9.6255 4.9349 4.8075 4.5073 4.19523.7857 (m) Lattice spacing (d) 15.9390 9.5631 4.9186 4.7972 4.49824.1874 3.7953 (n) Lattice spacing (d) 15.939 9.5838 4.9132 4.7920 4.49374.1874 3.7762 (o) Lattice spacing (d) 15.9967 9.6046 4.9024 4.80754.4982 4.1719 3.7293 (p) Lattice spacing (d) 16.0548 9.6255 4.93494.8075 4.5073 4.1992 3.8145 (q) Lattice spacing (d) 15.7684 9.54254.8282 4.4802 4.1757 3.7263 (r) Lattice spacing (d) 15.9390 9.58384.9132 4.8023 4.4937 4.1641 3.7730 (s) Lattice spacing (d) 15.93909.5838 4.9186 4.7920 4.4937 4.1835 3.7921 (t) Lattice spacing (d)15.9390 9.5838 4.9240 4.7920 4.4982 4.1874 3.7921 (u) Lattice spacing(d) 16.0548 9.6255 4.9186 4.7920 4.4982 4.1835 3.7985 (v) Latticespacing (d) 16.0548 9.6255 4.9294 4.7972 4.5073 4.1874 3.7985 (w)Lattice spacing (d) 16.0548 9.6255 4.9186 4.8075 4.4982 4.1835 3.8049(x) Lattice spacing (d) 15.9967 9.6046 4.9240 4.8023 4.4982 4.18743.7985 (y) Lattice spacing (d) 15.9390 9.5838 4.9186 4.7869 4.49374.1796 3.7985.
 9. An analgesic agent comprising the crystal according toclaim
 1. 10. An anti-cancer agent comprising the crystal according toclaim
 1. 11. An osteoarthritis therapeutic agent comprising the crystalaccording to claim 1.